JP5944921B2 - Neprilysin inhibitor - Google Patents

Description

(Background of the Invention)
(Field of Invention)
The present invention relates to a novel compound having neprilysin inhibitory activity. The present invention also provides pharmaceutical compositions comprising such compounds, processes and intermediates for preparing such compounds, and the treatment of such diseases as hypertension, heart failure, pulmonary hypertension, and kidney disease. Relates to methods of using such compounds.

(Technical level)
Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP) is an endothelial cell membrane association found in many organs and tissues including the brain, kidney, lung, gastrointestinal tract, heart, and peripheral vasculature Zn ²⁺ metallopeptidase. NEP degrades and inactivates several endogenous peptides such as enkephalins, circulating bradykinins, angiotensin peptides, and natriuretic peptides (the latter of which, for example, vasodilation and increased natriuresis / diuresis, and cardiac hypertrophy) And has several effects, including inhibition of ventricular fibrosis). Thus, NEP plays an important role in blood pressure homeostasis and circulatory health.

  NEP inhibitors such as thiorphan, candoxatril, and candoxatrilat have been investigated as potential therapeutic agents. Compounds that inhibit both NEP and angiotensin-I converting enzyme (ACE) are also known, and include omapatrilat, gempatrilat, and sampatrilat. This latter class of compounds, called vasopeptidase inhibitors, is described in [1].

Robl et al. (1999) Exp. Opin. Ther. Patents, 9 (12): 1665-1677

(Summary of the Invention)
The present invention provides novel compounds that have been found to possess neprilysin (NEP) enzyme inhibitory activity. Accordingly, the compounds of the present invention are expected to be useful and advantageous as therapeutic agents for treating conditions such as hypertension and heart failure.

  One aspect of the present invention is a compound of formula I:

（式中、
Ｒ^１は、−ＯＲ^７および−ＮＲ^８Ｒ^９から選択され、
Ｒ^２は、Ｈもしくは−Ｐ（Ｏ）（ＯＨ）_２であるか、またはＲ^２は、Ｒ^７と一緒になって、−ＣＲ^１８Ｒ^１９−を形成するか、もしくはＲ^８と一緒になって、−Ｃ（Ｏ）−を形成し、
Ｘは、−Ｃ_１〜９ヘテロアリールであり、
Ｒ^３は、存在しないか、またはＨ；ハロ；−Ｃ_０〜５アルキレン−ＯＨ；−ＮＨ_２；−Ｃ_１〜６アルキル；−ＣＦ_３；−Ｃ_３〜７シクロアルキル；−Ｃ_０〜２アルキレン−Ｏ−Ｃ_１〜６アルキル；−Ｃ（Ｏ）Ｒ^２０；−Ｃ_０〜１アルキレン−ＣＯＯＲ^２１；−Ｃ（Ｏ）ＮＲ^２２Ｒ^２３；−ＮＨＣ（Ｏ）Ｒ^２４；＝Ｏ；−ＮＯ_２；−Ｃ（ＣＨ_３）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ_３、−ＯＣＨ_３、−ＮＨＣ（Ｏ）ＣＨ_３、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで必要に応じて置換されているピラゾリル；メチルもしくはハロで必要に応じて置換されているチオフェニル；フラニル；ならびに−ＣＨ_２−モルホリニルから選択され、Ｒ^３は、存在する場合、炭素原子に結合し、
Ｒ^４は存在しないか、またはＨ；−ＯＨ；−Ｃ_１〜６アルキル；−Ｃ_１〜２アルキレン−ＣＯＯＲ^３５；−ＣＨ_２ＯＣ（Ｏ）ＣＨ（Ｒ^３６）ＮＨ_２；−ＯＣＨ_２ＯＣ（Ｏ）ＣＨ（Ｒ^３６）ＮＨ_２；−ＯＣＨ_２ＯＣ（Ｏ）ＣＨ_３；−ＣＨ_２ＯＰ（Ｏ）（ＯＨ）_２；−ＣＨ_２ＣＨ（ＯＨ）ＣＨ_２ＯＨ；−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）Ｏ−Ｃ_１〜６アルキル；ピリジニル；ならびにハロ、−ＣＯＯＲ^３５、−ＯＣＨ_３、−ＯＣＦ_３、および−ＳＣＦ_３から選択される１つもしくは複数の基で必要に応じて置換されているフェニルもしくはベンジルから選択され、Ｒ^４は、存在する場合、炭素または窒素原子に結合するか、
あるいはＲ^３およびＲ^４は、一緒になって、−フェニレン−Ｏ−（ＣＨ_２）_１〜３−または−フェニレン−Ｏ−ＣＨ_２−ＣＨＯＨ−ＣＨ_２−を形成し、
ａは０または１であり、Ｒ^５は、ハロ、−ＣＨ_３、−ＣＦ_３、および−ＣＮから選択され、
ｂは、０であるか、または１〜３の整数であり、各Ｒ^６は、独立して、ハロ、−ＯＨ、−ＣＨ_３、−ＯＣＨ_３、および−ＣＦ_３から選択され、
Ｒ^７は、Ｈ、−Ｃ_１〜８アルキル、−Ｃ_１〜３アルキレン−Ｃ_６〜１０アリール、−Ｃ_１〜３アルキレン−Ｃ_１〜９ヘテロアリール、−Ｃ_３〜７シクロアルキル、−［（ＣＨ_２）_２Ｏ］_１〜３ＣＨ_３、−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^１０、−Ｃ_１〜６アルキレン−ＮＲ^１２Ｒ^１３、−Ｃ_１〜６アルキレン−Ｃ（Ｏ）Ｒ^３１、−Ｃ_０〜６アルキレンモルホリニル、−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル、

(Where
R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ ;
R ² is H or —P (O) (OH) ₂ , or R ² is taken together with R ⁷ to form —CR ¹⁸ R ¹⁹ — or taken together with R ^8. -C (O)-
X is —C _1-9 heteroaryl,
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - NO ₂ ; —C (CH ₃ ) ═N (OH); 1 or 2 groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl in which optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; are optionally substituted with methyl or halo thiophenyl; pyrazolyl are optionally substituted with methyl furanyl; and -CH ₂ - Is selected from Ruhoriniru, R ^3, if present, bound to a carbon atom,
R ⁴ is absent or H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; —OCH ₂ OC ( _{^{O) CH (R 36) NH}} 2; -OCH 2 OC (O) CH 3; -CH 2 OP (O) (OH) 2; -CH 2 CH (OH) CH 2 OH; -CH [CH (CH 3 ₂ ] —NHC (O) O—C _1-6 alkyl; pyridinyl; and optionally in one or more groups selected from halo, —COOR ³⁵ , —OCH ₃ , —OCF ₃ , and —SCF _3. Optionally selected from phenyl or benzyl, R ⁴ , if present, is attached to a carbon or nitrogen atom,
Or R ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- ,
a is 0 or 1, R ⁵ is selected from halo, —CH ₃ , —CF ₃ , and —CN;
b is 0 or an integer from 1 to 3 and each R ⁶ is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ ;
R ⁷ is H, —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _3-7 cycloalkyl, — [ _{(CH 2) 2 O] 1~3} CH 3, -C 1~6 alkylene _{^{-OC (O) R 10, -C}} 1~6 alkylene ^-NR 12 ^R _{13, -C} ^1~6 alkylene -C (O) R ^31, _{-C Less than six} alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

から選択され、
Ｒ^１０は、−Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、−Ｃ_３〜７シクロアルキル、−Ｏ−Ｃ_３〜７シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ^１２Ｒ^１３、−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨ_２、−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）Ｏ−Ｃ_１〜６アルキル、および−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３から選択され、Ｒ^１２およびＲ^１３は、独立して、Ｈ、−Ｃ_１〜６アルキル、およびベンジルから選択されるか、またはＲ^１２およびＲ^１３は、−（ＣＨ_２）_３〜６−、−Ｃ（Ｏ）−（ＣＨ_２）_３−、もしくは−（ＣＨ_２）_２Ｏ（ＣＨ_２）_２−として一つになり、Ｒ^３１は、−Ｏ−Ｃ_１〜６アルキル、−Ｏ−ベンジル、および−ＮＲ^１２Ｒ^１３から選択され、Ｒ^３２は、−Ｃ_１〜６アルキルまたは−Ｃ_０〜６アルキレン−Ｃ_６〜１０アリールであり、
Ｒ^８は、Ｈ、−ＯＨ、−ＯＣ（Ｏ）Ｒ^１４、−ＣＨ_２ＣＯＯＨ、−Ｏ−ベンジル、−ピリジル、および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^１４は、Ｈ、−Ｃ_１〜６アルキル、−Ｃ_６〜１０アリール、−ＯＣＨ_２−Ｃ_６〜１０アリール、−ＣＨ_２Ｏ−Ｃ_６〜１０アリール、および−ＮＲ^１５Ｒ^１６から選択され、Ｒ^１５およびＲ^１６は、独立して、Ｈおよび−Ｃ_１〜４アルキルから選択され、
Ｒ^９は、Ｈ、−Ｃ_１〜６アルキル、および−Ｃ（Ｏ）−Ｒ^１７から選択され、Ｒ^１７は、Ｈ、−Ｃ_１〜６アルキル、−Ｃ_３〜７シクロアルキル、−Ｃ_６〜１０アリール、および−Ｃ_１〜９ヘテロアリールから選択され、
Ｒ^１８およびＲ^１９は、独立して、Ｈ、−Ｃ_１〜６アルキル、および−Ｏ−Ｃ_３〜７シクロアルキルから選択されるか、またはＲ^１８およびＲ^１９は、一緒になって＝Ｏを形成し、
Ｒ^２０は、Ｈおよび−Ｃ_１〜６アルキルから選択され、
Ｒ^２１およびＲ^３５は、独立して、Ｈ、−Ｃ_１〜６アルキル、−Ｃ_１〜３アルキレン−Ｃ_６〜１０アリール、−Ｃ_１〜３アルキレン−Ｃ_１〜９ヘテロアリール、−Ｃ_３〜７シクロアルキル、−［（ＣＨ_２）_２Ｏ］_１〜３ＣＨ_３、−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^２５；−Ｃ_１〜６アルキレン−ＮＲ^２７Ｒ^２８、−Ｃ_１〜６アルキレン−Ｃ（Ｏ）Ｒ^３３、−Ｃ_０〜６アルキレンモルホリニル、−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル、

Selected from
R ¹⁰ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ¹² R ^13. , —CH [CH (CH ₃ ) ₂ ] —NH ₂ , —CH [CH (CH ₃ ) ₂ ] —NHC (O) O—C _1-6 alkyl, and —CH (NH ₂ ) CH ₂ COOCH ₃ R ¹² and R ¹³ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ¹² and R ¹³ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³¹ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 12 ^{R 13, R 32} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ⁸ is selected from H, —OH, —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, -pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ , wherein R ¹⁴ is H, -C _{1 to 6 alkyl, -C 6 to 10} aryl _is selected from -OCH _{2 -C 6 to 10 aryl,} -CH _{2 O-C 6~10} aryl, and ^-NR 15 ^{R 16, R 15} and ^{R 16} _Are independently selected from H and —C _1-4 alkyl;
R ⁹ is selected from H, —C _1-6 alkyl, and —C (O) —R ¹⁷ , wherein R ¹⁷ is H, —C _1-6 alkyl, —C _3-7 cycloalkyl, —C ₆ Selected from _-10 aryl, and -C _1-9 heteroaryl,
R ¹⁸ and R ¹⁹ are independently selected from H, —C _1-6 alkyl, and —O—C _3-7 cycloalkyl, or R ¹⁸ and R ^{19 taken} together are ═O Form the
R ²⁰ is selected from H and —C _1-6 alkyl;
R ²¹ and R ³⁵ are independently H, —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{3. 7-cycloalkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene _{^{-OC (O) R 25; -C}} 1~6 alkylene _^-NR 27 ^R 28, _-C ^1~ ₆ alkylene-C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

から選択され、
Ｒ^２５は、−Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、−Ｃ_３〜７シクロアルキル、−Ｏ−Ｃ_３〜７シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ^２７Ｒ^２８、−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨ_２、−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）Ｏ−Ｃ_１〜６アルキル、および−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３から選択され、Ｒ^２７およびＲ^２８は、独立して、Ｈ、−Ｃ_１〜６アルキル、およびベンジルから選択されるか、またはＲ^２７およびＲ^２８は、−（ＣＨ_２）_３〜６−、−Ｃ（Ｏ）−（ＣＨ_２）_３−、もしくは−（ＣＨ_２）_２Ｏ（ＣＨ_２）_２−として一つになり、Ｒ^３３は、−Ｏ−Ｃ_１〜６アルキル、−Ｏ−ベンジル、および−ＮＲ^２７Ｒ^２８から選択され、Ｒ^３４は、−Ｃ_１〜６アルキルまたは−Ｃ_０〜６アルキレン−Ｃ_６〜１０アリールであり、
Ｒ^２２およびＲ^２３は、独立して、Ｈ、−Ｃ_１〜６アルキル、−ＣＨ_２ＣＯＯＨ、−（ＣＨ_２）_２ＯＨ；−（ＣＨ_２）_２ＯＣＨ_３、−（ＣＨ_２）_２ＳＯ_２ＮＨ_２、−（ＣＨ_２）_２Ｎ（ＣＨ_３）_２、−Ｃ_０〜１アルキレン−Ｃ_３〜７シクロアルキル、および−（ＣＨ_２）_２−イミダゾリルから選択されるか、またはＲ^２２およびＲ^２３は、一緒になって、ハロ、−ＯＨ、−ＣＯＯＨ、もしくは−ＣＯＮＨ_２で必要に応じて置換されており、環内に酸素原子を必要に応じて含有する、飽和もしくは部分的に不飽和の−Ｃ_３〜５ヘテロ環を形成し、
Ｒ^２４は、−Ｃ_１〜６アルキル；−Ｃ_０〜１アルキレン−Ｏ−Ｃ_１〜６アルキル；ハロまたは−ＯＣＨ_３で必要に応じて置換されているフェニル；および−Ｃ_１〜９ヘテロアリールから選択され、
Ｒ^３６は、Ｈ、−ＣＨ（ＣＨ_３）_２、フェニル、およびベンジルから選択され、
Ｒ^１、Ｒ^３、およびＲ^４の中の各アルキル基は、１〜８個のフルオロ原子で必要に応じて置換されており、
ビフェニル上のメチレンリンカーは、１または２つの−Ｃ_１〜６アルキル基またはシクロプロピルで必要に応じて置換されている）
または薬学的に許容されるその塩に関する。

Selected from
R ²⁵ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ²⁷ R ^28. , —CH [CH (CH ₃ ) ₂ ] —NH ₂ , —CH [CH (CH ₃ ) ₂ ] —NHC (O) O—C _1-6 alkyl, and —CH (NH ₂ ) CH ₂ COOCH ₃ R ²⁷ and R ²⁸ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ²⁷ and R ²⁸ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³³ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 27 ^{R 28, R 34} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ²² and R ²³ are independently H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH; — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ SO _2. NH ₂ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _0-1 alkylene-C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ²³ together, saturated or partially unsaturated, optionally substituted with halo, —OH, —COOH, or —CONH ₂ , optionally containing an oxygen atom in the ring A -C _3-5 heterocycle of
R ²⁴ is —C _1-6 alkyl; —C _0-1 alkylene-O—C _1-6 alkyl; phenyl optionally substituted with halo or —OCH ₃ ; and —C _1-9 heteroaryl Selected from
R ³⁶ is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl;
Each alkyl group in R ¹ , R ³ , and R ⁴ is optionally substituted with 1 to 8 fluoro atoms,
The methylene linker on biphenyl is optionally substituted with 1 or 2 —C _1-6 alkyl groups or cyclopropyl)
Or a pharmaceutically acceptable salt thereof.

  Another aspect of the present invention pertains to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of the present invention. Such a composition may contain other therapeutic agents as necessary. Accordingly, in yet another aspect of the invention, the pharmaceutical composition comprises a compound of the invention as a first therapeutic agent, one or more second therapeutic agents, and a pharmaceutically acceptable carrier. including. Another aspect of the present invention pertains to an active agent combination comprising a compound of the present invention and a second therapeutic agent. The compounds of the invention can be formulated together with or separately from the additional agent (s). When formulated separately, a pharmaceutically acceptable carrier can be included with the additional agent (s). Accordingly, yet another aspect of the present invention provides a combination of pharmaceutical compositions comprising a first pharmaceutical composition comprising a compound of the present invention and a first pharmaceutically acceptable carrier, and a second A combination comprising a therapeutic agent and a second pharmaceutical composition comprising a second pharmaceutically acceptable carrier. In another aspect, the invention relates to a kit comprising such a pharmaceutical composition, for example a kit wherein the first and second pharmaceutical compositions are separate pharmaceutical compositions.

  Since the compounds of the present invention possess NEP enzyme inhibitory activity, to treat patients suffering from a disease or disorder that is treated by inhibiting the NEP enzyme or by increasing the level of its peptide substrate. It is expected to be useful as a therapeutic agent. Accordingly, one aspect of the present invention is a method of treating a patient suffering from a disease or disorder that is treated by inhibiting NEP enzyme, comprising administering to the patient a therapeutically effective amount of a compound of the present invention. Relates to a method comprising: Another aspect of the invention relates to a method of treating hypertension, heart failure, or renal disease, comprising administering to a patient a therapeutically effective amount of a compound of the invention. Yet another aspect of the invention relates to a method for inhibiting a NEP enzyme in a mammal, comprising the step of administering to the mammal an NEP enzyme inhibitory amount of a compound of the invention.

  Since the compounds of the present invention possess NEP inhibitory activity, they are also useful as research tools. Accordingly, one aspect of the present invention pertains to methods of using a compound of the present invention as a research tool, comprising the step of performing a biological assay using the compound of the present invention. The compounds of the present invention can also be used to evaluate new chemicals. Accordingly, another aspect of the invention is a method for evaluating a test compound in a biological assay, wherein (a) obtaining a first assay value by performing a biological assay using the test compound. And (b) obtaining a second assay value by conducting a biological assay using the compound of the present invention, and (c) obtaining the first assay value obtained in step (a) by the step ( comparing with the second assay value obtained in b), wherein step (a) is performed before, after or simultaneously with step (b). Typical biological assays include NEP enzyme inhibition assays. Yet another aspect of the present invention is a method for studying a biological system or sample comprising a NEP enzyme, comprising: (a) contacting said biological system or sample with a compound of the present invention; And) determining the effect caused by said compound on a biological system or sample.

  Yet another aspect of the invention relates to processes and intermediates useful for preparing the compounds of the invention. Accordingly, another aspect of the invention is a process for preparing a compound of formula I comprising coupling a compound of formula 1 with a compound of formula 2 to produce a compound of formula I

（式中、Ｐ^１はＨであるか、またはｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基である）を含み、Ｐ^１がアミノ保護基である場合、前記式１の化合物を脱保護するステップをさらに含み、Ｒ^１〜Ｒ^６、ａ、ｂ、およびＸは式Ｉに対して定義された通りであるプロセスに関する。本発明の別の態様は、式Ｉの化合物の薬学的に許容される塩を調製するためのプロセスであって、式Ｉの化合物を遊離酸または塩基形態で、薬学的に許容される塩基または酸と接触させるステップを含むプロセスに関する。他の態様では、本発明は、本明細書中に記載されているプロセスのいずれかで調製される生成物、ならびにこのようなプロセスで使用される新規の中間体に関する。本発明の一態様では、新規中間体は、本明細書中で定義された通りの式１、６、７、８、もしくは９、またはその塩を有する。

Wherein P ¹ is H or an amino protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl. And wherein P ¹ is an amino protecting group further comprises deprotecting said compound of formula 1, wherein R ^{1 to} R ⁶ , a, b, and X are defined for formula I Regarding the process that is street. Another aspect of the invention is a process for preparing a pharmaceutically acceptable salt of a compound of formula I, wherein the compound of formula I is in the free acid or base form, a pharmaceutically acceptable base or It relates to a process comprising a step of contacting with an acid. In other aspects, the invention relates to products prepared by any of the processes described herein, as well as novel intermediates used in such processes. In one aspect of the invention, the novel intermediate has Formula 1, 6, 7, 8, or 9, or a salt thereof, as defined herein.

（式中、
Ｒ ^１ は、−ＯＲ ^７ および−ＮＲ ^８ Ｒ ^９ から選択され、
Ｒ ^２ は、Ｈもしくは−Ｐ（Ｏ）（ＯＨ） _２ であるか、または、Ｒ ^２ は、Ｒ ^７ と一緒になって、−ＣＲ ^１８ Ｒ ^１９ −を形成するか、もしくはＲ ^８ と一緒になって、−Ｃ（Ｏ）−を形成し、
Ｘは、−Ｃ _１〜９ ヘテロアリールであり、
Ｒ ^３ は、存在しないか、またはＨ；ハロ；−Ｃ _０〜５ アルキレン−ＯＨ；−ＮＨ _２ ；−Ｃ _１〜６ アルキル；−ＣＦ _３ ；−Ｃ _３〜７ シクロアルキル；−Ｃ _０〜２ アルキレン−Ｏ−Ｃ _１〜６ アルキル；−Ｃ（Ｏ）Ｒ ^２０ ；−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ ；−Ｃ（Ｏ）ＮＲ ^２２ Ｒ ^２３ ；−ＮＨＣ（Ｏ）Ｒ ^２４ ；＝Ｏ；−ＮＯ _２ ；−Ｃ（ＣＨ _３ ）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ _３ 、−ＯＣＨ _３ 、−ＮＨＣ（Ｏ）ＣＨ _３ 、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで必要に応じて置換されているピラゾリル；メチルもしくはハロで必要に応じて置換されているチオフェニル；フラニル；ならびに−ＣＨ _２ −モルホリニルから選択され、Ｒ ^３ は、存在する場合、炭素原子に結合し、
Ｒ ^４ は、存在しないか、またはＨ；−ＯＨ；−Ｃ _１〜６ アルキル；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；−ＣＨ _２ ＯＣ（Ｏ）ＣＨ（Ｒ ^３６ ）ＮＨ _２ ；−ＯＣＨ _２ ＯＣ（Ｏ）ＣＨ（Ｒ ^３６ ）ＮＨ _２ ；−ＯＣＨ _２ ＯＣ（Ｏ）ＣＨ _３ ；−ＣＨ _２ ＯＰ（Ｏ）（ＯＨ） _２ ；−ＣＨ _２ ＣＨ（ＯＨ）ＣＨ _２ ＯＨ；−ＣＨ［ＣＨ（ＣＨ _３ ） _２ ］−ＮＨＣ（Ｏ）Ｏ−Ｃ _１〜６ アルキル；ピリジニル；ならびにハロ、−ＣＯＯＲ ^３５ 、−ＯＣＨ _３ 、−ＯＣＦ _３ 、および−ＳＣＦ _３ から選択される１つもしくは複数の基で必要に応じて置換されているフェニルもしくはベンジルから選択され、Ｒ ^４ は、存在する場合、炭素または窒素原子に結合し、
あるいはＲ ^３ およびＲ ^４ は一緒になって、−フェニレン−Ｏ−（ＣＨ _２ ） _１〜３ −または−フェニレン−Ｏ−ＣＨ _２ −ＣＨＯＨ−ＣＨ _２ −を形成し、
ａは、０または１であり、Ｒ ^５ は、ハロ、−ＣＨ _３ 、−ＣＦ _３ 、および−ＣＮから選択され、
ｂは、０または１〜３の整数であり、各Ｒ ^６ は、独立して、ハロ、−ＯＨ、−ＣＨ _３ 、−ＯＣＨ _３ 、および−ＣＦ _３ から選択され、
Ｒ ^７ は、Ｈ、−Ｃ _１〜８ アルキル、−Ｃ _１〜３ アルキレン−Ｃ _６〜１０ アリール、−Ｃ _１〜３ アルキレン−Ｃ _１〜９ ヘテロアリール、−Ｃ _３〜７ シクロアルキル、−［（ＣＨ _２ ） _２ Ｏ］ _１〜３ ＣＨ _３ 、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^１０ 、−Ｃ _１〜６ アルキレン−ＮＲ ^１２ Ｒ ^１３ 、−Ｃ _１〜６ アルキレン−Ｃ（Ｏ）Ｒ ^３１ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、

から選択され、
Ｒ ^１０ は、−Ｃ _１〜６ アルキル、−Ｏ−Ｃ _１〜６ アルキル、−Ｃ _３〜７ シクロアルキル、−Ｏ−Ｃ _３〜７ シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ ^１２ Ｒ ^１３ 、−ＣＨ［ＣＨ（ＣＨ _３ ） _２ ］−ＮＨ _２ 、−ＣＨ［ＣＨ（ＣＨ _３ ） _２ ］−ＮＨＣ（Ｏ）Ｏ−Ｃ _１〜６ アルキル、および−ＣＨ（ＮＨ _２ ）ＣＨ _２ ＣＯＯＣＨ _３ から選択され、Ｒ ^１２ およびＲ ^１３ は、独立して、Ｈ、−Ｃ _１〜６ アルキル、およびベンジルから選択されるか、またはＲ ^１２ およびＲ ^１３ は、−（ＣＨ _２ ） _３〜６ −、−Ｃ（Ｏ）−（ＣＨ _２ ） _３ −、もしくは−（ＣＨ _２ ） _２ Ｏ（ＣＨ _２ ） _２ −として一つになり、Ｒ ^３１ は、−Ｏ−Ｃ _１〜６ アルキル、−Ｏ−ベンジル、および−ＮＲ ^１２ Ｒ ^１３ から選択され、Ｒ ^３２ は、−Ｃ _１〜６ アルキルまたは−Ｃ _０〜６ アルキレン−Ｃ _６〜１０ アリールであり、
Ｒ ^８ は、Ｈ、−ＯＨ、−ＯＣ（Ｏ）Ｒ ^１４ 、−ＣＨ _２ ＣＯＯＨ、−Ｏ−ベンジル、−ピリジル、および−ＯＣ（Ｓ）ＮＲ ^１５ Ｒ ^１６ から選択され、Ｒ ^１４ は、Ｈ、−Ｃ _１〜６ アルキル、−Ｃ _６〜１０ アリール、−ＯＣＨ _２ −Ｃ _６〜１０ アリール、−ＣＨ _２ Ｏ−Ｃ _６〜１０ アリール、および−ＮＲ ^１５ Ｒ ^１６ から選択され、Ｒ ^１５ およびＲ ^１６ は、独立して、Ｈおよび−Ｃ _１〜４ アルキルから選択され、
Ｒ ^９ は、Ｈ、−Ｃ _１〜６ アルキル、および−Ｃ（Ｏ）−Ｒ ^１７ から選択され、Ｒ ^１７ は、Ｈ、−Ｃ _１〜６ アルキル、−Ｃ _３〜７ シクロアルキル、−Ｃ _６〜１０ アリール、および−Ｃ _１〜９ ヘテロアリールから選択され、
Ｒ ^１８ およびＲ ^１９ は、独立して、Ｈ、−Ｃ _１〜６ アルキル、および−Ｏ−Ｃ _３〜７ シクロアルキルから選択されるか、またはＲ ^１８ およびＲ ^１９ は一緒になって、＝Ｏを形成し、
Ｒ ^２０ は、Ｈおよび−Ｃ _１〜６ アルキルから選択され、
Ｒ ^２１ およびＲ ^３５ は、独立して、Ｈ、−Ｃ _１〜６ アルキル、−Ｃ _１〜３ アルキレン−Ｃ _６〜１０ アリール、−Ｃ _１〜３ アルキレン−Ｃ _１〜９ ヘテロアリール、−Ｃ _３〜７ シクロアルキル、−［（ＣＨ _２ ） _２ Ｏ］ _１〜３ ＣＨ _３ 、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^２５ 、−Ｃ _１〜６ アルキレン−ＮＲ ^２７ Ｒ ^２８ 、−Ｃ _１〜６ アルキレン−Ｃ（Ｏ）Ｒ ^３３ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、

から選択され、
Ｒ ^２５ は、−Ｃ _１〜６ アルキル、−Ｏ−Ｃ _１〜６ アルキル、−Ｃ _３〜７ シクロアルキル、−Ｏ−Ｃ _３〜７ シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ ^２７ Ｒ ^２８ 、−ＣＨ［ＣＨ（ＣＨ _３ ） _２ ］−ＮＨ _２ 、−ＣＨ［ＣＨ（ＣＨ _３ ） _２ ］−ＮＨＣ（Ｏ）Ｏ−Ｃ _１〜６ アルキル、および−ＣＨ（ＮＨ _２ ）ＣＨ _２ ＣＯＯＣＨ _３ から選択され、Ｒ ^２７ およびＲ ^２８ は、独立して、Ｈ、−Ｃ _１〜６ アルキル、およびベンジルから選択されるか、またはＲ ^２７ およびＲ ^２８ は、−（ＣＨ _２ ） _３〜６ −、−Ｃ（Ｏ）−（ＣＨ _２ ） _３ −、もしくは−（ＣＨ _２ ） _２ Ｏ（ＣＨ _２ ） _２ −として一つになり、Ｒ ^３３ は、−Ｏ−Ｃ _１〜６ アルキル、−Ｏ−ベンジル、および−ＮＲ ^２７ Ｒ ^２８ から選択され、Ｒ ^３４ は、−Ｃ _１〜６ アルキルまたは−Ｃ _０〜６ アルキレン−Ｃ _６〜１０ アリールであり、
Ｒ ^２２ およびＲ ^２３ は、独立して、Ｈ、−Ｃ _１〜６ アルキル、−ＣＨ _２ ＣＯＯＨ、−（ＣＨ _２ ） _２ ＯＨ、−（ＣＨ _２ ） _２ ＯＣＨ _３ 、−（ＣＨ _２ ） _２ ＳＯ _２ ＮＨ _２ 、−（ＣＨ _２ ） _２ Ｎ（ＣＨ _３ ） _２ 、−Ｃ _０〜１ アルキレン−Ｃ _３〜７ シクロアルキル、および−（ＣＨ _２ ） _２ −イミダゾリルから選択されるか、またはＲ ^２２ およびＲ ^２３ は一緒になって、ハロ、−ＯＨ、−ＣＯＯＨ、もしくは−ＣＯＮＨ _２ で必要に応じて置換されており、環内に酸素原子を必要に応じて含有する、飽和もしくは部分的に不飽和の−Ｃ _３〜５ ヘテロ環を形成し、
Ｒ ^２４ は、−Ｃ _１〜６ アルキル；−Ｃ _０〜１ アルキレン−Ｏ−Ｃ _１〜６ アルキル；ハロまたは−ＯＣＨ _３ で必要に応じて置換されているフェニル；および−Ｃ _１〜９ ヘテロアリールから選択され、
Ｒ ^３６ は、Ｈ、−ＣＨ（ＣＨ _３ ） _２ 、フェニル、およびベンジルから選択され、
Ｒ ^１ 、Ｒ ^３ 、およびＲ ^４ の中の各アルキル基は、１〜８個のフルオロ原子で必要に応じて置換されており、
ビフェニル上のメチレンリンカーは、１または２つの−Ｃ _１〜６ アルキル基またはシクロプロピルで必要に応じて置換されている）
または薬学的に許容されるその塩。
（項目２）
Ｘが、ピラゾール、イミダゾール、トリアゾール、ベンゾトリアゾール、フラン、ピロール、テトラゾール、ピラジン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、イソチアゾール、オキサジアゾール、チアジアゾール、ピリダジン、ピリジン、ピリミジン、ピラン、ベンゾイミダゾール、ベンゾオキサゾール、ベンゾチアゾール、ピリジルイミダゾール、およびピリジルトリアゾールから選択される、項目１に記載の化合物。
（項目３）
Ｘが、ピラゾール、トリアゾール、ベンゾトリアゾール、フラン、テトラゾール、ピラジン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、オキサジアゾール、ピリダジン、ピリジン、ピリミジン、ベンゾオキサゾール、ピリジルイミダゾール、およびピリジルトリアゾールから選択される、項目２に記載の化合物。
（項目４）
式ＩＩＩ：

を有する、項目３に記載の化合物。
（項目５）
Ｒ ^１ が、−ＯＲ ^７ および−ＮＲ ^８ Ｒ ^９ から選択され、Ｒ ^７ がＨであり、Ｒ ^８ が、Ｈまたは−ＯＨであり、Ｒ ^９ がＨである、項目１から４のいずれか一項に記載の化合物。
（項目６）
Ｒ ^１ が−ＯＲ ^７ であり、Ｒ ^７ が、−Ｃ _１〜８ アルキル、−Ｃ _１〜３ アルキレン−Ｃ _６〜１０ アリール、−Ｃ _１〜３ アルキレン−Ｃ _１〜９ ヘテロアリール、−Ｃ _３〜７ シクロアルキル、−［（ＣＨ _２ ） _２ Ｏ］ _１〜３ ＣＨ _３ 、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^１０ 、−Ｃ _１〜６ アルキレン−ＮＲ ^１２ Ｒ ^１３ 、−Ｃ _１〜６ アルキレン−Ｃ（Ｏ）Ｒ ^３１ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、

から選択されるか、または
Ｒ ^１ が−ＮＲ ^８ Ｒ ^９ であり、Ｒ ^８ が、−ＯＣ（Ｏ）Ｒ ^１４ 、−ＣＨ _２ ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ ^１５ Ｒ ^１６ から選択され、Ｒ ^９ がＨであるか、または
Ｒ ^１ が−ＮＲ ^８ Ｒ ^９ であり、Ｒ ^８ が、−ＯＣ（Ｏ）Ｒ ^１４ 、−ＣＨ _２ ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ ^１５ Ｒ ^１６ から選択され、Ｒ ^９ が、−Ｃ _１〜６ アルキルもしくは−Ｃ（Ｏ）Ｒ ^１７ であり、
Ｒ ^１ が−ＮＲ ^８ Ｒ ^９ であり、Ｒ ^８ が、Ｈおよび−ＯＨから選択され、Ｒ ^９ が、−Ｃ _１〜６ アルキル、および−Ｃ（Ｏ）Ｒ ^１７ から選択され、
Ｒ ^１ が−ＯＲ ^７ であり、Ｒ ^２ がＲ ^７ と一緒になって、−ＣＲ ^１８ Ｒ ^１９ −を形成するか、または
Ｒ ^１ が−ＮＲ ^８ Ｒ ^９ であり、Ｒ ^２ がＲ ^８ と一緒になって、−Ｃ（Ｏ）−を形成する、項目１から４のいずれか一項に記載の化合物。
（項目７）
Ｒ ^１ が−ＯＲ ^７ であり、Ｒ ^７ が、Ｈ、−Ｃ _１〜８ アルキル、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^１０ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、および

から選択され、
Ｒ ^１０ が−Ｏ−Ｃ _３〜７ シクロアルキルであり、Ｒ ^３２ が−ＣＨ _３ である、項目１から４のいずれか一項に記載の化合物。
（項目８）
Ｒ ^１ が−ＮＲ ^８ Ｒ ^９ であり、Ｒ ^８ がＨであり、Ｒ ^９ がＨである、項目１から４のいずれか一項に記載の化合物。
（項目９）
Ｒ ^２ がＨである、項目１から８のいずれか一項に記載の化合物。
（項目１０）
Ｒ ^３ が、存在しないか、またはＨ；ハロ；−Ｃ _０〜５ アルキレン−ＯＨ；−ＮＨ _２ ；−Ｃ _１〜６ アルキル；−ＣＦ _３ ；−Ｃ _３〜７ シクロアルキル；−Ｃ _０〜２ アルキレン−Ｏ−Ｃ _１〜６ アルキル；−Ｃ（Ｏ）Ｒ ^２０ ；−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ ；−Ｃ（Ｏ）ＮＲ ^２２ Ｒ ^２３ ；−ＮＨＣ（Ｏ）Ｒ ^２４ ；＝Ｏ；−ＮＯ _２ ；−Ｃ（ＣＨ _３ ）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ _３ 、−ＯＣＨ _３ 、−ＮＨＣ（Ｏ）ＣＨ _３ 、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで必要に応じて置換されているピラゾリル；メチルもしくはハロで必要に応じて置換されているチオフェニル；フラニル；ならびに−ＣＨ _２ −モルホリニルから選択され、Ｒ ^２１ がＨである、項目１から９のいずれか一項に記載の化合物。
（項目１１）
Ｒ ^３ が−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ であり、Ｒ ^２１ が、−Ｃ _１〜６ アルキル、−Ｃ _１〜３ アルキレン−Ｃ _６〜１０ アリール、−Ｃ _１〜３ アルキレン−Ｃ _１〜９ ヘテロアリール、−Ｃ _３〜７ シクロアルキル、−［（ＣＨ _２ ） _２ Ｏ］ _１〜３ ＣＨ _３ 、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^２５ 、−Ｃ _１〜６ アルキレン−ＮＲ ^２７ Ｒ ^２８ 、−Ｃ _１〜６ アルキレン−Ｃ（Ｏ）Ｒ ^３３ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、

から選択される、項目１から９のいずれか一項に記載の化合物。
（項目１２）
Ｒ ^３ が、存在しないか、またはＨ；ハロ；−Ｃ _０〜５ アルキレン−ＯＨ；−ＮＨ _２ ；−Ｃ _１〜６ アルキル；−ＣＦ _３ ；−Ｃ _３〜７ シクロアルキル；−Ｃ _０〜２ アルキレン−Ｏ−Ｃ _１〜６ アルキル；−Ｃ（Ｏ）Ｒ ^２０ ；−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ ；−Ｃ（Ｏ）ＮＲ ^２２ Ｒ ^２３ ；−ＮＨＣ（Ｏ）Ｒ ^２４ ；＝Ｏ；−Ｃ（ＣＨ _３ ）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ _３ 、−ＯＣＨ _３ 、−ＮＨＣ（Ｏ）ＣＨ _３ 、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで置換されているピラゾリル；メチルもしくはハロで置換されているチオフェニル；フラニル；ならびに−ＣＨ _２ −モルホリニルから選択され、Ｒ ^２０ が−Ｃ _１〜６ アルキルであり、Ｒ ^２１ が、Ｈおよび−Ｃ _１〜６ アルキルから選択され、Ｒ ^２２ が、Ｈおよび−Ｃ _１〜６ アルキルから選択され、Ｒ ^２３ が、Ｈ、−Ｃ _１〜６ アルキル、−ＣＨ _２ ＣＯＯＨ、−（ＣＨ _２ ） _２ ＯＨ、−（ＣＨ _２ ） _２ ＯＣＨ _３ 、−（ＣＨ _２ ） _２ Ｎ（ＣＨ _３ ） _２ 、−Ｃ _３〜７ シクロアルキル、および−（ＣＨ _２ ） _２ −イミダゾリルから選択されるか、またはＲ ^２２ およびＲ ^２３ が一緒になって、アゼチジン、ピロリジン、ピペリジンもしくはモルホリン（これらはすべて、−ＯＨまたは−ＣＯＮＨ _２ で必要に応じて置換されている）を形成し、Ｒ ^２４ が、−Ｃ _１〜６ アルキル；−Ｃ _０〜１ アルキレン−Ｏ−Ｃ _１〜６ アルキル；ハロまたは−ＯＣＨ _３ で置換されているフェニル；およびピリジンから選択される、項目１から９のいずれか一項に記載の化合物。
（項目１３）
Ｒ ^４ が、存在しないか、またはＨ；−ＯＨ；−Ｃ _１〜６ アルキル；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；−ＣＨ _２ ＯＣ（Ｏ）ＣＨ（Ｒ ^３６ ）ＮＨ _２ ；−ＣＨ _２ ＣＨ（ＯＨ）ＣＨ _２ ＯＨ；ピリジニル；ならびにハロ、−ＣＯＯＲ ^３５ 、−ＯＣＨ _３ 、−ＯＣＦ _３ 、および−ＳＣＦ _３ から選択される１つもしくは複数の基で必要に応じて置換されているフェニルもしくはベンジルから選択され、Ｒ ^３５ がＨである、項目１から１２のいずれか一項に記載の化合物。
（項目１４）
Ｒ ^４ が、−ＯＣＨ _２ ＯＣ（Ｏ）ＣＨ _３ ；−ＣＨ _２ ＯＰ（Ｏ）（ＯＨ） _２ ；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；および少なくとも１つの−ＣＯＯＲ ^３５ 基で置換されているフェニルまたはベンジルから選択され、Ｒ ^３５ が、−Ｃ _１〜６ アルキル、−Ｃ _１〜３ アルキレン−Ｃ _６〜１０ アリール、−Ｃ _１〜３ アルキレン−Ｃ _１〜９ ヘテロアリール、−Ｃ _３〜７ シクロアルキル、−［（ＣＨ _２ ） _２ Ｏ］ _１〜３ ＣＨ _３ 、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^２５ 、−Ｃ _１〜６ アルキレン−ＮＲ ^２７ Ｒ ^２８ 、−Ｃ _１〜６ アルキレン−Ｃ（Ｏ）Ｒ ^３３ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、

から選択される、項目１から１２のいずれか一項に記載の化合物。
（項目１５）
Ｒ ^４ が、存在しないか、またはＨ；−ＯＨ；−Ｃ _１〜６ アルキル；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；−ＣＨ _２ ＯＣ（Ｏ）ＣＨ（Ｒ ^３６ ）ＮＨ _２ ；−ＣＨ _２ ＣＨ（ＯＨ）ＣＨ _２ ＯＨ；ピリジニル；１つのハロ基で必要に応じて置換されているフェニル；ならびにハロ、−ＣＯＯＨ、−ＯＣＨ _３ 、−ＯＣＦ _３ 、および−ＳＣＦ _３ から選択される１つもしくは複数の基で必要に応じて置換されているベンジルから選択され、Ｒ ^３５ がＨであり、Ｒ ^３６ が−ＣＨ（ＣＨ _３ ） _２ であるか、あるいはＲ ^３ およびＲ ^４ が一緒になって、−フェニレン−Ｏ−（ＣＨ _２ ） _１〜３ −または−フェニレン−Ｏ−ＣＨ _２ −ＣＨＯＨ−ＣＨ _２ −を形成する、項目１から１２のいずれか一項に記載の化合物。
（項目１６）
ａが０であるか、またはａが１であり、Ｒ ^５ が３−クロロである、項目１から１５のいずれか一項に記載の化合物。
（項目１７）
ｂが０であるか、またはｂが１であり、かつＲ ^６ が、３’−クロロ、３’−メチル、もしくは２’−メトキシであるか、またはｂが２であり、かつＲ ^６ が、２’−フルオロ−５’−クロロ、２’，５’−ジクロロ、２’−メチル−５’−クロロ、もしくは３’−クロロ−５’−ヒドロキシである、項目１から１６のいずれか一項に記載の化合物。
（項目１８）
前記ビフェニル上の前記メチレンリンカーが、２つのメチル基で置換されている、項目１から１７のいずれか一項に記載の化合物。
（項目１９）
Ｒ ^１ が−ＯＲ ^７ であり、Ｒ ^７ が、Ｈ、−Ｃ _１〜８ アルキル、−Ｃ _１〜６ アルキレン−ＯＣ（Ｏ）Ｒ ^１０ 、−Ｃ _０〜６ アルキレンモルホリニル、−Ｃ _１〜６ アルキレン−ＳＯ _２ −Ｃ _１〜６ アルキル、および

から選択され、
Ｒ ^１０ が−Ｏ−Ｃ _３〜７ シクロアルキルであり、Ｒ ^３２ が−ＣＨ _３ であり、Ｒ ^８ がＨであり、Ｒ ^９ がＨであり、
Ｒ ^２ がＨであり、
Ｘが、ピラゾール、トリアゾール、ベンゾトリアゾール、フラン、テトラゾール、ピラジン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、オキサジアゾール、ピリダジン、ピリジン、ピリミジン、ベンゾオキサゾール、ピリジルイミダゾール、およびピリジルトリアゾールから選択され、
Ｒ ^３ が、存在しないか、またはＨ；ハロ；−Ｃ _０〜５ アルキレン−ＯＨ；−ＮＨ _２ ；−Ｃ _１〜６ アルキル；−ＣＦ _３ ；−Ｃ _３〜７ シクロアルキル；−Ｃ _０〜２ アルキレン−Ｏ−Ｃ _１〜６ アルキル；−Ｃ（Ｏ）Ｒ ^２０ ；−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ ；−Ｃ（Ｏ）ＮＲ ^２２ Ｒ ^２３ ；−ＮＨＣ（Ｏ）Ｒ ^２４ ；＝Ｏ；−Ｃ（ＣＨ _３ ）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ _３ 、−ＯＣＨ _３ 、−ＮＨＣ（Ｏ）ＣＨ _３ 、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで置換されているピラゾリル；メチルもしくはハロで置換されているチオフェニル；フラニル；ならびに−ＣＨ _２ −モルホリニルから選択され、
Ｒ ^４ が、存在しないか、またはＨ；−ＯＨ；−Ｃ _１〜６ アルキル；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；−ＣＨ _２ ＯＣ（Ｏ）ＣＨ（Ｒ ^３６ ）ＮＨ _２ ；−ＣＨ _２ ＣＨ（ＯＨ）ＣＨ _２ ＯＨ；ピリジニル；１つのハロ基で必要に応じて置換されているフェニル；ならびにハロ、−ＣＯＯＨ、−ＯＣＨ _３ 、−ＯＣＦ _３ 、および−ＳＣＦ _３ から選択される１つもしくは複数の基で必要に応じて置換されているベンジルから選択されるか、
あるいはＲ ^３ およびＲ ^４ が、一緒になって、−フェニレン−Ｏ−（ＣＨ _２ ） _１〜３ −または−フェニレン−Ｏ−ＣＨ _２ −ＣＨＯＨ−ＣＨ _２ −を形成し、
ａが０であるか、またはａが１であり、かつＲ ^５ が３−クロロであり、
ｂが０であるか、またはｂが１であり、かつＲ ^６ が、３’−クロロ、３’−メチル、もしくは２’−メトキシであるか、またはｂが２であり、かつＲ ^６ が、２’−フルオロ−５’−クロロ、２’，５’−ジクロロ、２’−メチル−５’−クロロ、もしくは３’−クロロ−５’−ヒドロキシであり、
Ｒ ^２０ が−Ｃ _１〜６ アルキルであり、
Ｒ ^２１ が、Ｈおよび−Ｃ _１〜６ アルキルから選択され、
Ｒ ^２２ が、Ｈおよび−Ｃ _１〜６ アルキルから選択され、Ｒ ^２３ が、Ｈ、−Ｃ _１〜６ アルキル、−ＣＨ _２ ＣＯＯＨ、−（ＣＨ _２ ） _２ ＯＨ、−（ＣＨ _２ ） _２ ＯＣＨ _３ 、−（ＣＨ _２ ） _２ Ｎ（ＣＨ _３ ） _２ 、−Ｃ _３〜７ シクロアルキル、および−（ＣＨ _２ ） _２ −イミダゾリルから選択されるか、またはＲ ^２２ およびＲ ^２３ が一緒になって、アゼチジン、ピロリジン、ピペリジンもしくはモルホリン（これらはすべて、−ＯＨまたは−ＣＯＮＨ _２ で必要に応じて置換されている）を形成し、
Ｒ ^２４ が、−Ｃ _１〜６ アルキル；−Ｏ−Ｃ _１〜６ アルキル；−ＣＨ _２ −Ｏ−Ｃ _１〜６ アルキル；ハロまたは−ＯＣＨ _３ で置換されているフェニル；およびピリジニルから選択され、
Ｒ ^３５ がＨであり、
Ｒ ^３６ が−ＣＨ（ＣＨ _３ ） _２ であり、
前記ビフェニル上の前記メチレンリンカーが、２つのメチル基で必要に応じて置換されている、項目１に記載の化合物。
（項目２０）
Ｒ ^１ が−ＯＲ ^７ であり、
Ｒ ^２ がＨであり、
Ｘが、ピラゾール、トリアゾール、ベンゾトリアゾール、イソオキサゾール、ピリダジン、ピリミジン、およびピリジルトリアゾールから選択され、
Ｒ ^３ が、Ｈ；ハロ；−Ｃ _０〜５ アルキレン−ＯＨ；−Ｃ _１〜６ アルキル；−ＣＦ _３ ；−Ｃ _３〜７ シクロアルキル；−Ｃ _０〜２ アルキレン−Ｏ−Ｃ _１〜６ アルキル；−Ｃ（Ｏ）Ｒ ^２０ ；−Ｃ _０〜１ アルキレン−ＣＯＯＲ ^２１ ；−Ｃ（Ｏ）ＮＲ ^２２ Ｒ ^２３ ；−ＮＨＣ（Ｏ）Ｒ ^２４ ；＝Ｏ；−Ｃ（ＣＨ _３ ）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、および−ＯＣＨ _３ から独立して選択される１または２つの基で必要に応じて置換されているフェニル；ピリジニル；ピラジニル；ならびにメチルまたはハロで置換されているチオフェニルから選択され、
Ｒ ^４ が、Ｈ；−ＯＨ；−Ｃ _１〜６ アルキル；−Ｃ _１〜２ アルキレン−ＣＯＯＲ ^３５ ；−ＣＨ _２ ＣＨ（ＯＨ）ＣＨ _２ ＯＨ；ピリジニル；および１つのハロ基で必要に応じて置換されているフェニルから選択されるか、またはＲ ^３ およびＲ ^４ が一緒になって、−フェニレン−Ｏ−（ＣＨ _２ ） _１〜３ −を形成し、
ａが０であるか、またはａが１であり、かつＲ ^５ が３−クロロであり、
ｂが０であるか、またはｂが１であり、かつＲ ^６ が、３’−クロロ、３’−メチル、もしくは２’−メトキシであるか、またはｂは２であり、かつＲ ^６ が、２’−フルオロ−５’−クロロ、２’，５’−ジクロロ、２’−メチル−５’−クロロ、もしくは３’−クロロ−５’−ヒドロキシであり、
Ｒ ^２０ が−Ｃ _１〜６ アルキルであり、
Ｒ ^２１ がＨであり、
Ｒ ^２２ が、Ｈおよび−Ｃ _１〜６ アルキルから選択され、Ｒ ^２３ が、−Ｃ _１〜６ アルキル、−（ＣＨ _２ ） _２ ＯＣＨ _３ 、および−Ｃ _３〜７ シクロアルキルから選択されるか、またはＲ ^２２ およびＲ ^２３ が、一緒になって、アゼチジン、ピロリジン、もしくはピペリジン（これらはすべて、−ＯＨまたは−ＣＯＮＨ _２ で必要に応じて置換されている）を形成し、
Ｒ ^２４ が、ハロまたは−ＯＣＨ _３ で置換されているフェニルであり、
Ｒ ^３５ がＨであり、
前記ビフェニル上の前記メチレンリンカーが、２つのメチル基で必要に応じて置換されている、項目１に記載の化合物。
（項目２１）
式１の化合物を、式２の化合物とカップリングして、式Ｉの化合物を生成するステップ

（式中、Ｐ ^１ はＨであるか、またはｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基である）を含み、Ｐ ^１ がアミノ保護基である場合、前記式１の化合物を脱保護するステップをさらに含む、項目１から２０のいずれか一項に記載の化合物を調製するためのプロセス。
（項目２２）
式１：

（式中、Ｐ ^１ はＨであるか、またはｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基である）を有する、項目１から２０のいずれか一項に記載の化合物の合成に有用な中間体またはその塩。
（項目２３）

から選択される化合物またはその塩（式中、Ｒ ^１Ｐ は、−Ｏ−Ｐ ^３ 、−ＮＨＰ ^２ 、および−ＮＨ（Ｏ−Ｐ ^４ ）から選択され、Ｒ ^３Ｐ は、−Ｃ _０〜５ アルキレン−Ｏ−Ｐ ^４ 、−Ｃ _０〜１ アルキレン−ＣＯＯ−Ｐ ^３ 、および−Ｏ−Ｐ ^４ で置換されているフェニルから選択され、Ｒ ^４Ｐ は、−Ｏ−Ｐ ^４ ；−Ｃ _１〜２ アルキレン−ＣＯＯ−Ｐ ^３ ；および−ＣＯＯ−Ｐ ^３ で置換されているフェニルまたはベンジルから選択され、Ｐ ^２ は、ｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基であり、Ｐ ^３ は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ ^４ は、−Ｃ _１〜６ アルキル、トリＣ _１〜６ アルキルシリル、−Ｃ _１〜６ アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基である）を脱保護するステップを含む、項目１から２０のいずれか一項に記載の化合物を調製するためのプロセス。
（項目２４）

から選択される、項目１から２０のいずれか一項に記載の化合物の合成に有用な中間体またはその塩（式中、Ｒ ^１Ｐ は、−Ｏ−Ｐ ^３ 、−ＮＨＰ ^２ 、および−ＮＨ（Ｏ−Ｐ ^４ ）から選択され、Ｒ ^３Ｐ は、−Ｃ _０〜５ アルキレン−Ｏ−Ｐ ^４ 、−Ｃ _０〜１ アルキレン−ＣＯＯ−Ｐ ^３ 、および−Ｏ−Ｐ ^４ で置換されているフェニルから選択され、Ｒ ^４Ｐ は、−Ｏ−Ｐ ^４ ；−Ｃ _１〜２ アルキレン−ＣＯＯ−Ｐ ^３ ；および−ＣＯＯ−Ｐ ^３ で置換されているフェニルまたはベンジルから選択され、Ｐ ^２ は、ｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基であり、Ｐ ^３ は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ ^４ は、−Ｃ _１〜６ アルキル、トリＣ _１〜６ アルキルシリル、−Ｃ _１〜６ アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基である）。
（項目２５）
項目１から２０のいずれか一項に記載の化合物と、薬学的に許容される担体とを含む薬学的組成物。
（項目２６）
アデノシン受容体アンタゴニスト、α−アドレナリン受容体アンタゴニスト、β _１ −アドレナリン受容体アンタゴニスト、β _２ −アドレナリン受容体アゴニスト、二重作用性β−アドレナリン受容体アンタゴニスト／α _１ −受容体アンタゴニスト、進行糖化終末産物ブレーカー、アルドステロンアンタゴニスト、アルドステロンシンターゼ阻害剤、アミノペプチダーゼＮ阻害剤、アンドロゲン、アンジオテンシン変換酵素阻害剤および二重作用性アンジオテンシン変換酵素／ネプリライシン阻害剤、アンジオテンシン変換酵素２アクチベーターおよび刺激物質、アンジオテンシン−ＩＩワクチン、抗凝血剤、抗糖尿病剤、下痢止剤、抗緑内障剤、抗脂質剤、抗侵害受容性剤、抗血栓剤、ＡＴ _１ 受容体アンタゴニストおよび二重作用性ＡＴ _１ 受容体アンタゴニスト／ネプリライシン阻害剤および多官能性アンジオテンシン受容体遮断剤、ブラジキニン受容体アンタゴニスト、カルシウムチャネル遮断剤、キマーゼ阻害剤、ジゴキシン、利尿剤、ドーパミンアゴニスト、エンドセリン変換酵素阻害剤、エンドセリン受容体アンタゴニスト、ＨＭＧ−ＣｏＡ還元酵素阻害剤、エストロゲン、エストロゲン受容体アゴニストおよび／またはアンタゴニスト、モノアミン再取り込み阻害剤、筋弛緩剤、ナトリウム利尿ペプチドおよびこれらの類似体、ナトリウム利尿ペプチドクリアランス受容体アンタゴニスト、ネプリライシン阻害剤、一酸化窒素ドナー、非ステロイド性抗炎症剤、Ｎ−メチルｄ−アスパラギン酸受容体アンタゴニスト、オピオイド受容体アゴニスト、ホスホジエステラーゼ阻害剤、プロスタグランジン類似体、プロスタグランジン受容体アゴニスト、レニン阻害剤、選択的セロトニン再取り込み阻害剤、ナトリウムチャネル遮断剤、可溶性グアニル酸シクラーゼ刺激物質およびアクチベーター、三環式抗うつ剤、バソプレッシン受容体アンタゴニストならびにこれらの組合せから選択される治療剤をさらに含む、項目２５に記載の薬学的組成物。
（項目２７）
前記治療剤がＡＴ _１ 受容体アンタゴニストである、項目２６に記載の薬学的組成物。
（項目２８）
療法での使用のための、項目１から２０のいずれか一項に記載の化合物。
（項目２９）
高血圧、心不全、または腎疾患の処置における使用のための、項目２８に記載の化合物。
（項目３０）
高血圧、心不全、または腎疾患を処置するための医薬の製造のための、項目１から２０のいずれか一項に記載の化合物の使用。

Yet another aspect of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament, in particular for the manufacture of a medicament useful for treating hypertension, heart failure, or renal disease. Relates to the use of salt. Another aspect of the present invention pertains to the use of compounds of the present invention to inhibit a NEP enzyme in a mammal. Yet another aspect of the present invention relates to the use of a compound of the present invention as a research tool. Other aspects and embodiments of the invention are disclosed herein.
In a preferred embodiment of the present invention, for example, the following items are provided.
(Item 1)
Compounds of formula I:

(Where
R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ ;
R ² is H or —P (O) (OH) ₂ , or R ² together with R ⁷ forms —CR ¹⁸ R ¹⁹ —, or together with R ⁸ To form -C (O)-
X is —C _1-9 heteroaryl,
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - NO ₂ ; —C (CH ₃ ) ═N ( OH); 1 or 2 groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl in which optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; are optionally substituted with methyl or halo thiophenyl; pyrazolyl are optionally substituted with methyl furanyl; and -CH ₂ - Is selected from Ruhoriniru, R ^3, if present, bound to a carbon atom,
R ⁴ is absent or H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; —OCH ₂ OC _{^{(O) CH (R 36)}} NH 2; -OCH 2 OC (O) CH 3; -CH 2 OP (O) (OH) 2; -CH 2 CH (OH) CH 2 OH; -CH [CH (CH _{3) 2] -NHC (O)} O-C 1~6 alkyl; pyridinyl; and _{^{halo, -COOR 35, -OCH 3, -OCF}} 3, and requires one or more groups selected from -SCF ₃ Selected from phenyl or benzyl, optionally substituted, R ⁴ , if present, is attached to a carbon or nitrogen atom;
Or R ³ and R ⁴ together form -phenylene- O- (CH ₂ ) _1-3 -or -phenylene- O-CH ₂ -CHOH-CH _2-
a is 0 or 1, R ⁵ is selected from halo, —CH ₃ , —CF ₃ , and —CN;
b is an integer of 0 or 1-3, and each R ⁶ is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ ;
R ⁷ is H, —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _3-7 cycloalkyl, — [ _{(CH 2) 2 O] 1~3} CH 3, -C 1~6 alkylene _{^{-OC (O) R 10, -C}} 1~6 alkylene ^-NR 12 ^R _{13, -C} ^1~6 alkylene -C (O) R ^31, _{-C Less than six} alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

Selected from
R ¹⁰ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ¹² R ^13. from _{-CH [CH (CH 3) 2} ] -NH 2, -CH [CH (CH 3) 2] -NHC (O) O-C 1~6 alkyl, and _{-CH (NH 2) CH 2 COOCH} 3 R ¹² and R ¹³ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ¹² and R ¹³ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³¹ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 12 ^{R 13, R 32} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ⁸ is selected from H, —OH, —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, -pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ , wherein R ¹⁴ is H, -C _{1 to 6 alkyl, -C 6 to 10} aryl _is selected from -OCH _{2 -C 6 to 10 aryl,} -CH _{2 O-C 6~10} aryl, and ^-NR 15 ^{R 16, R 15} and ^{R 16} _Are independently selected from H and —C _1-4 alkyl;
R ⁹ is selected from H, —C _1-6 alkyl, and —C (O) —R ¹⁷ , wherein R ¹⁷ is H, —C _1-6 alkyl, —C _3-7 cycloalkyl, —C ₆ Selected from _-10 aryl, and -C _1-9 heteroaryl,
R ¹⁸ and R ¹⁹ are independently selected from H, —C _1-6 alkyl, and —O—C _3-7 cycloalkyl, or R ¹⁸ and R ¹⁹ together are ═O Form the
R ²⁰ is selected from H and —C _1-6 alkyl;
R ²¹ and R ³⁵ are independently H, —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{3. -7} cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ²⁵ , -C _1-6 alkylene-NR ²⁷ R ²⁸ , -C _{1 6} alkylene-C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

Selected from
R ²⁵ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ²⁷ R ^28. from _{-CH [CH (CH 3) 2} ] -NH 2, -CH [CH (CH 3) 2] -NHC (O) O-C 1~6 alkyl, and _{-CH (NH 2) CH 2 COOCH} 3 R ²⁷ and R ²⁸ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ²⁷ and R ²⁸ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³³ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 27 ^{R 28, R 34} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ²² and R ²³ are independently H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ SO _2. NH ₂ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _0-1 alkylene-C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ²³ together are saturated or partially unsaturated, optionally substituted with halo, —OH, —COOH, or —CONH ₂ , optionally containing an oxygen atom in the ring. -C _3-5 heterocycle is formed,
R ²⁴ is —C _1-6 alkyl; —C _0-1 alkylene-O—C _1-6 alkyl; phenyl optionally substituted with halo or —OCH ₃ ; and —C _1-9 heteroaryl Selected from
R ³⁶ is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl;
Each alkyl group in R ¹ , R ³ , and R ⁴ is optionally substituted with 1 to 8 fluoro atoms,
The methylene linker on biphenyl is optionally substituted with 1 or 2 -C _1-6 alkyl groups or cyclopropyl)
Or a pharmaceutically acceptable salt thereof.
(Item 2)
X is pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridazine, pyridine, pyrimidine, pyran, benzimidazole, benzo Item 2. The compound according to item 1, selected from oxazole, benzothiazole, pyridylimidazole, and pyridyltriazole.
(Item 3)
An item wherein X is selected from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole 2. The compound according to 2.
(Item 4)
Formula III:

4. The compound according to item 3, wherein
(Item 5)
Any one of items 1 to 4, wherein R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, R ⁸ is H or —OH, and R ⁹ is H. The compound according to item.
(Item 6)
R ¹ is —OR ⁷ and R ⁷ is —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{3 -7} cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ¹⁰ , -C _1-6 alkylene-NR ¹² R ¹³ , -C _{1 6} alkylene-C (O) R ³¹ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

Selected from or
R ¹ is —NR ⁸ R ⁹ , R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; ⁹ is H or
R ¹ is —NR ⁸ R ⁹ , R ⁸ is selected from —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ ; ⁹ is —C _1-6 alkyl or —C (O) R ¹⁷ ;
R ¹ is —NR ⁸ R ⁹ , R ⁸ is selected from H and —OH, R ⁹ is selected from —C _1-6 alkyl, and —C (O) R ¹⁷ ;
R ¹ is —OR ⁷ and R ² together with R ⁷ forms —CR ¹⁸ R ¹⁹ —, or
The compound according to any one of items 1 to 4, wherein R ¹ is —NR ⁸ R ⁹ and R ² together with R ⁸ forms —C (O) —.
(Item 7)
R ¹ is —OR ⁷ and R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylenemorpholinyl, —C _{1- 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, and

Selected from
_5. The compound according to any one of items 1 to 4, wherein R ¹⁰ is —O—C _3-7 cycloalkyl and R ³² is —CH ₃ .
(Item 8)
5. The compound according to any one of items 1 to 4, wherein R ¹ is —NR ⁸ R ⁹ , R ⁸ is H, and R ⁹ is H.
(Item 9)
9. A compound according to any one of items 1 to 8, wherein R ² is H.
(Item 10)
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - NO ₂ ; —C (CH ₃ ) ═N ( OH); 1 or 2 groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl in which optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; are optionally substituted with methyl or halo thiophenyl; pyrazolyl are optionally substituted with methyl furanyl; and -CH ₂ - Is selected from Ruhoriniru, R ²¹ is H, A compound according to any one of Items 1 9.
(Item 11)
R ³ is —C _0-1 alkylene-COOR ²¹ , R ²¹ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9. Heteroaryl, -C _3-7 cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ²⁵ , -C _1-6 alkylene-NR ²⁷ R ^28, _{-C 1 to 6} alkylene ^{_{-C (O) R 33, -C}} 0~6 alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

10. The compound according to any one of items 1 to 9, selected from:
(Item 12)
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - _{C (CH 3) = N (} OH); _{halo, -OH, -CF 3, -OCH 3} , optionally with -NHC (O) CH _3, and one or two groups independently selected from phenyl phenyl which is substituted Te; naphthalenyl; pyridinyl; pyrazinyl; thiophenyl substituted with methyl or halo; pyrazolyl substituted with methyl furanyl; and -CH 2 _- is selected from morpholinyl, R ²⁰ is A C _{1 to 6} ^{alkyl, R 21} is selected from H and _{-C 1 to 6} ^{alkyl, R 22} is selected from H and _{-C 1 to 6} ^{alkyl, R 23} is H, _{-C. 1 to 6} alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _3-7 cycloalkyl, and — (CH ₂ ) selected from ₂ -imidazolyl or R ²² and R ^{23 taken} together to be azetidine, pyrrolidine, piperidine or morpholine, all of which are optionally substituted with —OH or —CONH ₂ ) is ^{formed, R 24} _{is, -C 1 to 6 alkyl;} or and pyridine; _{-C 0 to 1} alkylene _{-O-C 1 to 6} alkyl; halo or phenyl substituted with -OCH ₃ It is selected, the compounds according to any one of Items 1 9.
(Item 13)
R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) _CH 2 OH; pyridinyl; and _{^{halo, -COOR 35, -OCH 3, -OCF}} 3, and one or more of the phenyl or benzyl are optionally substituted with a group selected from -SCF ₃ 13. The compound according to any one of items 1 to 12 , wherein R ³⁵ is H.
(Item 14)
R ⁴ is substituted with —OCH ₂ OC (O) CH ₃ ; —CH ₂ OP (O) (OH) ₂ ; —C _1-2 alkylene-COOR ³⁵ ; and at least one —COOR ³⁵ group. Or selected from benzyl and R ³⁵ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _3-7 cyclo. _{alkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene _{^{-OC (O) R 25, -C}} 1~6 alkylene ^-NR 27 ^R _{28, -C} ^1~6 alkylene - C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

13. The compound according to any one of items 1 to 12, selected from:
(Item 15)
R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) CH ₂ OH; pyridinyl; phenyl optionally substituted with one halo group; and one or more selected from halo, —COOH, —OCH ₃ , —OCF ₃ , and —SCF ₃ R ³⁵ is H and R ³⁶ is —CH (CH ₃ ) ₂ , or R ³ and R ⁴ together are selected from the group consisting of phenylene -O- _{(CH 2)} 1~3 - or - phenylene _{-O-CH 2 -CHOH-CH 2} - to form a compound according to any one of items 1 12.
(Item 16)
16. A compound according to any one of items 1 to 15, wherein a is 0 or a is 1 and R ⁵ is 3-chloro.
(Item 17)
b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is Any one of items 1 to 16, which is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy. Compound described in 1.
(Item 18)
18. A compound according to any one of items 1 to 17, wherein the methylene linker on the biphenyl is substituted with two methyl groups.
(Item 19)
R ¹ is —OR ⁷ and R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylenemorpholinyl, —C _{1- 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, and

Selected from
R ¹⁰ is —O—C _3-7 cycloalkyl, R ³² is —CH ₃ , R ⁸ is H, R ⁹ is H,
R ² is H;
X is selected from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole;
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - _{C (CH 3) = N (} OH); _{halo, -OH, -CF 3, -OCH 3} , optionally with -NHC (O) CH _3, and one or two groups independently selected from phenyl phenyl which is substituted Te; naphthalenyl; pyridinyl; pyrazinyl; thiophenyl substituted with methyl or halo; pyrazolyl substituted with methyl furanyl; and -CH 2 _- is selected from morpholinyl,
R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) CH ₂ OH; pyridinyl; phenyl optionally substituted with one halo group; and one or more selected from halo, —COOH, —OCH ₃ , —OCF ₃ , and —SCF ₃ Selected from benzyl optionally substituted with a group of
Or R ³ and R ⁴ together form -phenylene- O- (CH ₂ ) _1-3 -or -phenylene- O-CH ₂ -CHOH-CH _2-
a is 0 or a is 1 and R ⁵ is 3-chloro;
b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is 2′-fluoro-5′-chloro, 2 ′, 5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy,
R ²⁰ is —C _1-6 alkyl;
R ²¹ is selected from H and —C _1-6 alkyl;
R ²² is selected from H and —C _1-6 alkyl, and R ²³ is H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH _3. , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ^{23 taken} together to form an azetidine , Pyrrolidine, piperidine or morpholine, all of which are optionally substituted with —OH or —CONH ₂ ,
R ²⁴ is selected from —C _1-6 alkyl; —O—C _1-6 alkyl; —CH ₂ —O—C _1-6 alkyl; phenyl substituted with halo or —OCH ₃ ; and pyridinyl;
R ³⁵ is H;
R ³⁶ is —CH (CH ₃ ) ₂ ;
2. A compound according to item 1, wherein the methylene linker on the biphenyl is optionally substituted with two methyl groups.
(Item 20)
R ¹ is -OR ⁷ ;
R ² is H;
X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole;
R ³ is H; halo; -C _0-5 alkylene-OH; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene-O-C _1-6 alkyl _{^{; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; -C (CH 3) = N (OH ); Selected from phenyl optionally substituted with one or two groups independently selected from halo, —OH, and —OCH ₃ ; selected from pyridinyl; pyrazinyl; and thiophenyl substituted with methyl or halo And
R ⁴ is optionally substituted with H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ CH (OH) CH ₂ OH; pyridinyl; and one halo group. Selected from phenyl, or R ³ and R ⁴ together form -phenylene-O— (CH ₂ ) _1-3 —
a is 0 or a is 1 and R ⁵ is 3-chloro;
b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is 2′-fluoro-5′-chloro, 2 ′, 5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy,
R ²⁰ is —C _1-6 alkyl;
R ²¹ is H;
R ²² is selected from H and —C _1-6 alkyl; and R ²³ is selected from —C _1-6 alkyl, — (CH ₂ ) ₂ OCH ₃ , and —C _3-7 cycloalkyl, Or R ²² and R ²³ together form azetidine, pyrrolidine, or piperidine, all of which are optionally substituted with —OH or —CONH ₂ ,
R ²⁴ is phenyl substituted with halo or —OCH ₃ ;
R ³⁵ is H;
2. A compound according to item 1, wherein the methylene linker on the biphenyl is optionally substituted with two methyl groups.
(Item 21)
Coupling a compound of formula 1 with a compound of formula 2 to form a compound of formula I

Wherein P ¹ is H or an amino protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl. 21. and when P ¹ is an amino protecting group, the method for preparing a compound according to any one of items 1 to 20 further comprising the step of deprotecting said compound of formula 1.
(Item 22)
Formula 1:

Wherein P ¹ is H or an amino protecting group selected from t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl. An intermediate useful for the synthesis of a compound according to any one of Items 1 to 20 or a salt thereof.
(Item 23)

Or a salt thereof, wherein R ^1P is selected from —O—P ³ , —NHP ² , and —NH (O—P ⁴ ), wherein R ^3P is —C _0-5 alkylene- Selected from phenyl substituted with O—P ⁴ , —C _0-1 alkylene-COO—P ³ , and —O—P ⁴ , wherein R ^4P is —O—P ⁴ ; —C _1-2 alkylene- COO—P ³ ; and phenyl or benzyl substituted with —COO—P ³ , wherein P ² is t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyl is an amino protecting group selected from dimethyl silyl, ^{P 3} is methyl, ethyl, t- butyl, benzyl, p- methoxybenzyl, 9- fluorenyl Rumechiru, trimethylsilyl, a t- butyldimethylsilyl, and carboxy protecting group selected from diphenylmethyl, ^{P 4} _{is, -C 1 to 6} alkyl, tri _{C 1 to 6} alkyl _{silyl, -C 1 to 6} alkanoyl, benzoyl A compound according to any one of items 1 to 20, comprising the step of deprotecting (which is a hydroxyl protecting group selected from benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl). Process for preparing.
(Item 24)

An intermediate useful for the synthesis of a compound according to any one of Items 1 to 20 or a salt thereof selected from: wherein R ^1P is —O—P ³ , —NHP ² , and —NH ( ^{O-P 4)} is selected ^{from, R 3-Way} _{is, -C 0 to 5} alkylene ^-O-P _4, phenyl substituted with _{-C 0 to 1} alkylene ^{-COO-P 3,} and ^{-O-P 4} R ^4P is selected from —O—P ⁴ ; —C _1-2 alkylene-COO—P ³ ; and phenyl or benzyl substituted with —COO—P ³ , wherein P ² is t-butoxy carbonyl, trityl, benzyloxycarbonyl, a 9-fluorenylmethoxycarbonyl, formyl, amino-protecting group selected from trimethylsilyl and t- butyldimethylsilyl, P ³ is methyl, ethyl t- butyl, benzyl, p- methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, a carboxy protecting group selected from t- butyldimethylsilyl, and diphenylmethyl, ^{P 4} _{is, -C 1 to 6} alkyl, A hydroxyl protecting group selected from tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl).
(Item 25)
21. A pharmaceutical composition comprising the compound according to any one of items 1 to 20 and a pharmaceutically acceptable carrier.
(Item 26)
Adenosine receptor antagonist, α-adrenergic receptor antagonist, β ₁ -adrenergic receptor antagonist, β ₂ -adrenergic receptor agonist, dual acting β-adrenergic receptor antagonist / α ₁ -receptor antagonist, advanced glycation end product Breaker, aldosterone antagonist, aldosterone synthase inhibitor, aminopeptidase N inhibitor, androgen, angiotensin converting enzyme inhibitor and dual acting angiotensin converting enzyme / neprilysin inhibitor, angiotensin converting enzyme 2 activator and stimulator, angiotensin-II vaccine , anticoagulants, antidiabetic agents, antidiarrheals, anti-glaucoma agents, anti-lipid agents, anti-nociceptive agents, antithrombotic agents, AT ₁ receptor antagonists and dual-acting AT ₁ Toner antagonist / neprilysin inhibitor and multifunctional angiotensin receptor blocker, bradykinin receptor antagonist, calcium channel blocker, chymase inhibitor, digoxin, diuretic, dopamine agonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, HMG -CoA reductase inhibitors, estrogens, estrogen receptor agonists and / or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and their analogs, natriuretic peptide clearance receptor antagonists, neprilysin inhibitors, one Nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterers Inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blockers, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, 26. The pharmaceutical composition of item 25 further comprising a therapeutic agent selected from a vasopressin receptor antagonist and combinations thereof.
(Item 27)
27. A pharmaceutical composition according to item 26, wherein the therapeutic agent is an AT ₁ receptor antagonist.
(Item 28)
21. A compound according to any one of items 1 to 20 for use in therapy.
(Item 29)
29. A compound according to item 28 for use in the treatment of hypertension, heart failure or renal disease.
(Item 30)
21. Use of a compound according to any one of items 1 to 20 for the manufacture of a medicament for treating hypertension, heart failure or renal disease.

(Detailed description of the invention)
Definitions When describing the compounds, compositions, methods and processes of the invention, the following terms have the following meanings unless otherwise indicated. Further, as used herein, the singular forms “a”, “an”, and “the” include the corresponding plural forms unless the context in which it is used clearly dictates otherwise. The terms “comprising”, “including” and “having” are intended to be inclusive and mean that there may be additional elements other than the listed elements. All numbers expressing amounts, characteristics, eg molecular weights, reaction conditions, etc. of the components used herein are in all cases modified with the term “about” unless otherwise indicated. Please understand. Accordingly, the numbers described herein are approximations that can vary depending on the desired properties sought to be obtained by the present invention. At least, and without attempting to limit the application of the equivalent principle of the claims, each number is interpreted at least in light of the reported significant figures and by applying ordinary rounding techniques Should.

The term “alkyl” means a monovalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkyl groups usually contain from 1 to 10 carbon atoms and include, for example, —C _1-4 alkyl, —C _1-5 alkyl, —C _2-5 alkyl, — C _{1 to 6 alkyl,} such as _{-C 1 to 8} alkyl addition _{-C 1 to 10} alkyl. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, Examples include n-nonyl and n-decyl.

Where a particular number of carbon atoms is intended for a particular term as used herein, the number of carbon atoms is shown preceding the term as a subscript. For example, the term “—C _1-6 alkyl” means an alkyl group having 1-6 carbon atoms, and the term “—C _3-7 cycloalkyl” means 3-7 carbon atoms. Each having a carbon atom of any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkylene groups usually contain 0 to 10 carbon atoms, for example, —C _0-1 alkylene-, —C _0-6 alkylene-, —C _1-3 alkylene- , And -C _1-6 alkylene-. Representative alkylene groups include, by way of example, methylene, ethane-1,2-diyl (“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane. -1,5-diyl and the like. Where the term alkylene includes zero carbons, such as —C _0-1 alkylene-, such terms mean that there are no carbon atoms, ie an alkylene group joins a group separated by the term alkylene. It should be understood that it is intended not to exist other than covalently.

The term “aryl” means a monovalent aromatic hydrocarbon having a single ring (ie, phenyl) or one or more fused rings. Fused ring systems include those that are fully unsaturated (eg, naphthalene), as well as those that are partially unsaturated (eg, 1,2,3,4-tetrahydronaphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms and include, for example, —C _6-10 aryl and the like. Representative aryl groups include, for example, phenyl and naphthalen-1-yl, naphthalen-2-yl, and the like.

The term “cycloalkyl” means a monovalent saturated carbocyclic hydrocarbon group. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms and include, for example, —C _3-5 cycloalkyl, —C _3-6 cycloalkyl, and —C _3-7 cyclo Alkyl is mentioned. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

  The term “halo” means fluoro, chloro, bromo and iodo.

The term “heterocycle” refers to monovalent unsaturated (aromatic) heterocycles having a single ring or two fused rings, as well as monovalent saturated and partially unsaturated rings having one or more fused rings. It is intended to include groups. The heterocycle can contain a total of 3 to 15 ring atoms, of which 1 to 14 are ring carbon atoms and 1 to 4 are ring heteroatoms selected from nitrogen, oxygen or sulfur It is. However, usually the heterocycle contains a total of 3 to 10 ring atoms, of which 1 to 9 are ring carbon atoms and 1 to 4 are ring heteroatoms. The point of attachment is any available carbon or nitrogen ring atom. Typical heterocycle, for _{example, -C 1 to 7 heterocycle, -C 3 to 5 heterocyclic, -C 2 to 6 heterocycle, -C 3 to 12 heterocycle, -C 5 to 9} heterocycle, - C _1-9 heterocycle, -C _1-11 heterocycle, -C _1-14 heterocycle and the like can be mentioned.

Monovalent unsaturated heterocycles are also commonly referred to as “heteroaryl” groups. Unless otherwise defined, heteroaryl groups typically contain a total of 5 to 10 ring atoms, of which 1 to 9 are ring carbon atoms and 1 to 4 are ring heteroatoms, for example , -C _1-9 heteroaryl and -C _5-9 heteroaryl. Exemplary heteroaryl groups include, by way of example, pyrrole (eg, 3-pyrrolyl and 2H-pyrrol-3-yl), imidazole (eg, 2-imidazolyl), furan (eg, 2-furyl and 3-furyl), Thiophene (eg, 2-thienyl), triazole (eg, 1,2,3-triazolyl and 1,2,4-triazolyl), pyrazole (eg, 1H-pyrazol-3-yl), oxazole (eg, 2-oxazolyl) ), Isoxazole (eg, 3-isoxazolyl), thiazole (eg, 2-thiazolyl and 4-thiazolyl), and isothiazole (eg, 3-isothiazolyl), pyridine (eg, 2-pyridyl, 3-pyridyl, and 4) -Pyridyl), pyridylimidazole, pyridyltriazol , Pyrazine, pyridazine (eg, 3-pyridazinyl), pyrimidine (eg, 2-pyrimidinyl), tetrazole, triazine (eg, 1,3,5-triazinyl), indolyl (eg, 1H-indol-2-yl, 1H- Indol-4-yl and 1H-indol-5-yl), benzofuran (eg benzofuran-5-yl), benzothiophene (eg benzo [b] thien-2-yl and benzo [b] thien-5-yl) ), Benzimidazole, benzoxazole, benzothiazole, benzotriazole, quinoline (for example, 2-quinolyl), isoquinoline, quinazoline, quinoxaline and the like.

Monovalent saturated heterocycles usually contain a total of 3 to 10 ring atoms, of which 2 to 9 are ring carbon atoms and 1 to 4 are ring heteroatoms, such as -C _{3- 5-} heterocycle is mentioned. Representative monovalent saturated heterocycles include, for example, monovalent species of pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline and the like. In some cases, the moieties may be described as being taken together to form a saturated —C _3-5 heterocycle that optionally contains an oxygen atom in the ring. As such a group,

が挙げられる。

Is mentioned.

Monovalent partially unsaturated heterocycles usually contain a total of 3 to 10 ring atoms, of which 2 to 11 are ring carbon atoms, and 1 to 3 are ring heteroatoms, For example, _-C3-5 heterocycle and _-C2-12 heterocycle are mentioned. Representative monovalent partially unsaturated heterocycles include, by way of example, pyran, benzopyran, benzodioxole (eg, benzo [1,3] dioxol-5-yl), tetrahydropyridazine, 2,5- Dihydro-1H-pyrrole, dihydroimidazole, dihydrotriazole, dihydrooxazole, dihydroisoxazole, dihydrothiazole, dihydroisothiazole, dihydrooxadiazole, dihydrothiadiazole, tetrahydropyridazine, hexahydropyrroloquinoxaline, and dihydrooxadiazabenzo [e ] Azulene. In some cases, moieties may be described as those taken together to form a partially unsaturated —C _3-5 heterocycle. As such a group,

が挙げられる。

Is mentioned.

The term “optionally substituted” means that the group in question can be unsubstituted or once or several times, such as 1 to 3 times, or 1 to 5 times, or 1 to 8 times. It can be substituted. For example, a phenyl group “optionally substituted” with a halo atom may be unsubstituted or may contain 1, 2, 3, 4, or 5 halo atoms and may be “ An “optionally substituted” alkyl group can be unsubstituted or can contain 1, 2, 3, 4, 5, 6, 7, or 8 fluoro atoms. Similarly, 1 or "optionally substituted" group in the two -C _{1 to 6} alkyl groups, can be unsubstituted or contain one or two -C _{1 to 6} alkyl groups obtain.

  As used herein, the phrases “having a formula” or “having a structure” are not intended to be limiting, as the term “including” is commonly used. As used. For example, if one structure is depicted, it should be understood that all stereoisomeric and tautomeric forms are encompassed unless otherwise stated.

  The term “pharmaceutically acceptable” as used in the present invention refers to a substance that is not biologically or otherwise unacceptable. For example, the term “pharmaceutically acceptable carrier” can be incorporated into a composition to interact unacceptably with other components of the composition without causing unacceptable biological effects. Rather, it refers to a substance that is administered to a patient. Such pharmaceutically acceptable substances typically include substances that meet the required standards for toxicological and manufacturing testing and are identified as suitable inactive ingredients by the US Food and Drug Administration.

  The term “pharmaceutically acceptable salt” means a salt prepared from a base or acid that is acceptable for administration to a patient, such as a mammal (eg, a salt is acceptable for a given dosage regimen). Mammal safety). However, it is to be understood that the salts encompassed by the present invention need not be pharmaceutically acceptable salts, such as salts of intermediate compounds that are not intended for administration to a patient. Pharmaceutically acceptable salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Furthermore, if the compound of formula I contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, a zwitterion can be formed, which is described herein. It is included in the term “salt” used in the book. As salts derived from pharmaceutically acceptable inorganic bases, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts , Sodium salt, and zinc salt. Salts derived from pharmaceutically acceptable organic bases such as primary, secondary and tertiary amines including substituted amines, cyclic amines, naturally occurring amines, such as arginine, betaine, caffeine , Choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine Lysine, methylglucamine, morpholine, piperazine, piperazine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, Salts such as Rometamin and the like. Salts derived from pharmaceutically acceptable inorganic acids include boric acid, carbonic acid, hydrohalic acid (hydrobromic acid, hydrochloric acid, hydrofluoric acid or hydroiodic acid), nitric acid, phosphoric acid, Examples include sulfamic acid and sulfuric acid salts. Salts derived from pharmaceutically acceptable organic acids include aliphatic hydroxyl acids (eg, citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (eg, , Acetic acid, butyric acid, formic acid, propionic acid and trifluoroacetic acid), amino acids such as aspartic acid and glutamic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid, and Triphenylacetic acid), aromatic hydroxyl acids (eg, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acid (Eg fumaric acid, maleic acid, oxalic acid and succinic acid Acid), glucuronic acid, mandelic acid, mucinic acid, nicotinic acid, orotic acid, pamonic acid, pantothenic acid, sulfonic acid (eg, benzenesulfonic acid, camphorsulfonic acid, edylic acid, ethanesulfonic acid, isethionic acid, And salts such as methanesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid and p-toluenesulfonic acid) and xinafolic acid.

As used herein, the term “prodrug” refers to an inactive (or significantly less active) drug that is converted into the active form of the drug in the body under physiological conditions, eg, normal metabolic processes. It is intended to mean a precursor. Such compounds may not possess pharmacological activity with NEP, but can be administered orally or parenterally and then metabolized in the body, resulting in compounds having pharmacological activity with NEP Can be formed. Typical prodrugs include esters such as C _1-6 alkyl esters and aryl-C _1-6 alkyl esters. In one embodiment, the active compound has a free carboxyl, the prodrug is an ester derivative thereof, i.e., the prodrug is an ester, such as _{-C (O) OCH 2 CH 3} . Such ester prodrugs are then converted to the free carboxyl compounds by solvolysis or under physiological conditions. The term is also intended to include certain protected derivatives of compounds of Formula I that can be made prior to the final deprotection step. Accordingly, all protected derivatives and prodrugs of compounds of formula I are included within the scope of the invention.

  The term “therapeutically effective amount” means an amount sufficient to effect treatment when administered to a patient in need of treatment, ie, the amount of drug required to obtain the desired therapeutic effect. For example, a therapeutically effective amount for treating hypertension is, for example, the amount of compound required to reduce, inhibit, eliminate, or prevent the symptoms of hypertension, or to treat the underlying cause of hypertension. It is. In one embodiment, the therapeutically effective amount is the amount of drug required to reduce blood pressure or the amount of drug required to maintain normal blood pressure. On the other hand, the term “effective amount” means an amount sufficient to obtain the desired result, although this desired result may not necessarily be a therapeutic result. For example, when studying a system containing a NEP enzyme, an “effective amount” may be the amount required to inhibit the enzyme.

  The term “treating” or “treatment” as used herein means treating or treating a disease or medical condition (eg, hypertension) in a patient, such as a mammal (particularly a human), Including one or more of the following: (a) preventing the disease or medical condition from occurring, ie preventing the recurrence of the disease or medical condition, or propensity to become a disease or medical condition Preventive treatment of a patient; (b) ameliorate the disease or medical condition, ie, eliminate or cause a regression of the disease or medical condition in the patient; (c) suppress the disease or medical condition; I.e. delaying or stopping the progression of the disease or medical condition in the patient; or (d) symptom of the disease or medical condition in the patient Be reduced. For example, the term “treating hypertension” includes preventing hypertension from occurring, improving hypertension, suppressing hypertension, and reducing symptoms of high blood pressure (eg, lowering blood pressure). Become. The term “patient” is in need of treatment or disease prevention, or is currently undergoing treatment for the prevention or treatment of a disease of a particular disease or medical condition, and the compounds of the invention are evaluated in an assay. It is intended to include mammals such as humans, which are or are test subjects being used, such as animal models.

  All other terms used herein are intended to have their ordinary meaning as understood by one of ordinary skill in the art to which they relate.

  In one aspect, the invention provides a compound of formula I:

または薬学的に許容されるその塩に関する。

Or a pharmaceutically acceptable salt thereof.

  As used herein, the term “compound of the invention” refers to all compounds encompassed by Formula I, such as the species embodied in Formulas Ia-d, and Formulas II and III, and these species. Including compounds encompassed by In addition, the compounds of the present invention may also contain several basic or acidic groups (eg amino or carboxyl groups) and thus such compounds can be used as free bases or free acids or various Can exist in any salt form. All such salt forms are included within the scope of the present invention. Furthermore, the compounds of the invention may also exist as prodrugs. Accordingly, those skilled in the art will not be able to refer to a compound herein, such as “a compound of the invention” or “a compound of formula I”, unless otherwise indicated. It will be appreciated that the compounds include pharmaceutically acceptable salts and prodrugs. Furthermore, the term “or pharmaceutically acceptable salts and / or prodrugs thereof” is intended to include all permutations of salts and prodrugs, such as pharmaceutically acceptable salts of prodrugs and the like. . Furthermore, solvates of compounds of formula I are included within the scope of the invention.

  The compounds of formula I can contain one or more chiral centers and therefore these compounds can be prepared and used in various stereoisomeric forms. Accordingly, the present invention also relates to racemic mixtures, pure stereoisomers (eg, enantiomers and diastereoisomers), stereoisomer rich mixtures, and the like, unless otherwise indicated. If a chemical structure is depicted herein without any stereochemistry, it should be understood that all possible stereoisomers are encompassed by such structures. Thus, for example, terms such as “a compound of formula I”, “a compound of formula II” and the like are intended to include all possible stereoisomers of the compound. Similarly, if a particular stereoisomer is shown or named herein, lesser amounts of other stereoisomers may be present in the compositions of the invention unless otherwise indicated. However, one skilled in the art will appreciate that the usefulness of the composition as a whole is not excluded by the presence of such other isomers. Individual stereoisomers can be obtained by a number of methods well known in the art, including chiral chromatography using an appropriate chiral stationary phase or carrier, or diastereoisomerism thereof. Chemical conversion to the body, separation of these diastereoisomers by conventional means such as chromatography or recrystallization, and subsequent regeneration of the original stereoisomer.

  Further, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms, and topoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated. included. For example, X is:

と描写されている（Ｒ^４は水素）場合、化合物は、互変異性体形態、例えば

Where R ⁴ is hydrogen, the compound is in a tautomeric form, eg

などでも存在し得ることを理解されたい。

It should be understood that there may be such as.

More specifically, the compound of formula I may contain at least two chiral centers as indicated by the symbols ^* and ^** in the following formula.

１つの立体異性体では、^＊および^＊＊の記号で特定された両炭素原子は、（Ｒ）配置を有する。本発明のこの実施形態は、式Ｉａで示される。

In one stereoisomer, both carbon atoms identified by the symbols ^* and ^** have the (R) configuration. This embodiment of the invention is represented by Formula Ia.

本実施形態では、化合物は、^＊および^＊＊の炭素原子において（Ｒ，Ｒ）配置を有するか、またはこれら炭素原子において（Ｒ，Ｒ）配置を有する立体異性形態を豊富に含む。

In this embodiment, the compound is rich in stereoisomeric forms having (R, R) configuration at the ^* and ^** carbon atoms or having (R, R) configuration at these carbon atoms.

In another stereoisomer, both carbon atoms identified by the symbols ^* and ^** have the (S) configuration. This embodiment of the invention is shown by formula Ib.

本実施形態では、化合物は、^＊および^＊＊炭素原子において（Ｓ，Ｓ）配置を有するか、またはこれら炭素原子において（Ｓ，Ｓ）配置を有する立体異性形態を豊富に含む。

In this embodiment, the compound is rich in stereoisomeric forms having (S, S) configuration at the ^* and ^** carbon atoms or having (S, S) configuration at these carbon atoms.

In yet another stereoisomer, the carbon atom identified by the symbol * has the (S) configuration and the carbon atom identified by the symbol ^** has the (R) configuration. This embodiment of the invention is represented by Formula Ic.

本実施形態では、化合物は、^＊および^＊＊炭素原子において（Ｓ，Ｒ）配置を有するか、またはこれら炭素原子において（Ｓ，Ｒ）配置を有する立体異性形態を豊富に含む。

In this embodiment, the compound is rich in stereoisomeric forms having (S, R) configuration at ^* and ^** carbon atoms or having (S, R) configuration at these carbon atoms.

In yet another stereoisomer, the carbon atom identified by the symbol ^* has the (R) configuration and the carbon atom identified by the symbol ^** has the (S) configuration. This embodiment of the invention is represented by Formula Id.

本実施形態では、化合物は、^＊および^＊＊炭素原子において（Ｒ，Ｓ）配置を有するか、またはこれら炭素原子において（Ｒ，Ｓ）配置を有する立体異性形態を豊富に含む。

In this embodiment, the compound is rich in stereoisomeric forms having the (R, S) configuration at the ^* and ^** carbon atoms or having the (R, S) configuration at these carbon atoms.

  The compounds of formulas Ia and Ib are enantiomers and, therefore, in separate embodiments, the present invention provides each individual enantiomer (ie, Ia or Ib), a racemic mixture of Ia and Ib, or predominantly Ia Or a mixture of Ia and Ib rich in enantiomers, predominantly containing Ib. Similarly, compounds of formula Ic and Id are enantiomers, and thus, in separate embodiments, the present invention provides each individual enantiomer (ie, Ic or Id), a racemic mixture of Ic and Id, or It relates to an enantiomerically enriched mixture of Ic and Id, predominantly Ic or predominantly Id.

In some embodiments, in order to optimize the therapeutic activity of the compounds of the present invention, for example to treat hypertension, the carbon atoms identified with the ^* and ^** symbols may be of a certain (R , R), (S, S), (S, R), or (R, S) configurations, or it may be desirable to include abundant stereoisomeric forms having such configurations. For example, in one embodiment, the compounds of the invention have the (S, R) configuration of Formula Ic, or are rich in stereoisomeric forms having the (S, R) configuration, and in another embodiment, the present invention The compounds of the invention have the (R, S) configuration of formula Id or are rich in stereoisomeric forms having the (R, S) configuration. In other embodiments, the compounds of the invention exist as a racemic mixture, eg, as a mixture of enantiomers of formulas Ia and Ib, or as a mixture of enantiomers of formulas Ic and Id.

The compounds of the present invention, as well as the compounds used in their synthesis, are isotopically labeled compounds, i.e., one or more atoms having an atomic mass that differs from the atomic mass found primarily in nature. Also included are abundant compounds. Examples of isotopes that can be incorporated into compounds of Formula I are, for example, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³⁵ S, ³⁶ Cl, and ¹⁸ F or the like. Of particular interest are compounds of formula I rich in tritium or carbon-14, which can be used, for example, for tissue distribution studies, especially compounds of formula I rich in deuterium at the site of metabolism. (Eg, resulting in compounds with higher metabolic stability), and compounds of formula I rich in isotopes that emit positrons, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N (these are eg positrons) Can be used in radiation tomography (PET) studies).

  The nomenclature used herein to name the compounds of the present invention is illustrated in the Examples herein. This nomenclature was derived using commercially available AutoNom software (MDL, San Leandro, California).

Exemplary Embodiments The following substituents and values are intended to provide representative examples of various aspects and embodiments of the invention. These representative values are intended to further define and illustrate such aspects and embodiments, and are not intended to exclude other embodiments or to limit the scope of the invention. In this regard, the suggestion that a particular value or substituent is preferred is not intended in any way to exclude other values or substituents from the invention unless specifically indicated.

  In one aspect, the invention relates to compounds of formula I.

Ｒ^１は、−ＯＲ^７および−ＮＲ^８Ｒ^９から選択される。Ｒ^７部分は、
Ｈ；
−Ｃ_１〜８アルキル、例えば、−ＣＨ_３、−ＣＨ_２ＣＨ_３、−（ＣＨ_２）_２ＣＨ_３、−ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＣＨ（ＣＨ_３）_２、−（ＣＨ_２）_３ＣＨ_３、−（ＣＨ_２）_４ＣＨ_３、−（ＣＨ_２）_２ＣＨ（ＣＨ_３）_２、−（ＣＨ_２）_５ＣＨ_３、および−（ＣＨ_２）_６ＣＨ_３；
−Ｃ_１〜３アルキレン−Ｃ_６〜１０アリール、例えば、ベンジル；
−Ｃ_１〜３アルキレン−Ｃ_１〜９ヘテロアリール、例えば、−ＣＨ_２−ピリジニルおよび−（ＣＨ_２）_２−ピリジニル；
−Ｃ_３〜７シクロアルキル、例えば、シクロペンチル；
−［（ＣＨ_２）_２Ｏ］_１〜３ＣＨ_３、例えば、−（ＣＨ_２）_２ＯＣＨ_３および−［（ＣＨ_２）_２Ｏ］_２ＣＨ_３；
−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^１０、例えば、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）ＣＨ_２ＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）（ＣＨ_２）_２ＣＨ_３、−ＣＨ_２ＣＨ（ＣＨ_３）ＯＣ（Ｏ）ＣＨ_２ＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）ＯＣＨ_３、−ＣＨ_２ＯＣ（Ｏ）ＯＣＨ_２ＣＨ_３、−ＣＨ（ＣＨ_３）ＯＣ（Ｏ）ＯＣＨ_２ＣＨ_３、−ＣＨ（ＣＨ_３）ＯＣ（Ｏ）Ｏ−ＣＨ（ＣＨ_３）_２、−ＣＨ_２ＣＨ（ＣＨ_３）ＯＣ（Ｏ）−シクロペンチル、−ＣＨ_２ＯＣ（Ｏ）Ｏ−シクロプロピル、−ＣＨ（ＣＨ_３）−ＯＣ（Ｏ）−Ｏ−シクロヘキシル、−ＣＨ_２ＯＣ（Ｏ）Ｏ−シクロペンチル、−ＣＨ_２ＣＨ（ＣＨ_３）ＯＣ（Ｏ）−フェニル、−ＣＨ_２ＯＣ（Ｏ）Ｏ−フェニル、−ＣＨ_２ＯＣ（Ｏ）−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨ_２、−ＣＨ_２ＯＣ（Ｏ）−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）ＯＣＨ_３、および−ＣＨ（ＣＨ_３）ＯＣ（Ｏ）−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３；
−Ｃ_１〜６アルキレン−ＮＲ^１２Ｒ^１３、例えば、−（ＣＨ_２）_２−Ｎ（ＣＨ_３）_２、

R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ . R ⁷ part is
H;
-C _{1 to 8} alkyl, _{e.g., -CH 3, -CH 2 CH 3} , - (CH 2) 2 CH 3, -CH (CH 3) 2, -CH 2 CH (CH 3) 2, - (CH 2 ) ₃ CH ₃ , — (CH ₂ ) ₄ CH ₃ , — (CH ₂ ) ₂ CH (CH ₃ ) ₂ , — (CH ₂ ) ₅ CH ₃ , and — (CH ₂ ) ₆ CH ₃ ;
-C _{1 to 3} alkylene _{-C 6 to 10} aryl, such as benzyl;
-C _{1 to 3} alkylene _{-C 1 to 9} heteroaryl, for example, -CH ₂ - pyridinyl and - _{(CH 2) 2} - pyridinyl;
_{-C3-7cycloalkyl} , such as cyclopentyl;
_{- [(CH 2) 2 O} ] 1~3 CH 3, for _{example, - (CH 2) 2 OCH} 3 and _{- [(CH 2) 2 O} ] 2 CH 3;
-C _{1 to 6} alkylene -OC ^{(O) R 10,} for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) CH 2 CH 3, -CH 2 OC (O) (CH 2) 2 _{CH 3, -CH 2 CH (CH} 3) OC (O) CH 2 CH 3, -CH 2 OC (O) OCH 3, -CH 2 OC (O) OCH 2 CH 3, -CH (CH 3) OC ( _{O) OCH 2 CH 3, -CH} (CH 3) OC (O) OCH (CH 3) 2, -CH 2 CH (CH 3) OC (O) - _cyclopentyl, -CH 2 OC (O) O- Cyclopropyl, —CH (CH ₃ ) —OC (O) —O-cyclohexyl, —CH ₂ OC (O) O-cyclopentyl, —CH ₂ CH (CH ₃ ) OC (O) -phenyl, —CH ₂ OC ( O) O- _{phenyl, -CH 2 OC (O) -CH} [ _{H (CH 3) 2] -NH} 2, -CH 2 OC (O) -CH [CH (CH 3) 2] -NHC (O) OCH 3, and _{-CH (CH 3) OC (O} ) -CH ( NH _{2) CH 2} COOCH _3;
-C _{1 to 6} alkylene ^-NR 12 ^{R 13,} for _{example, - (CH 2) 2 -N} (CH 3) 2,

−Ｃ_１〜６アルキレン−Ｃ（Ｏ）Ｒ^３１、例えば、−ＣＨ_２Ｃ（Ｏ）ＯＣＨ_３、−ＣＨ_２Ｃ（Ｏ）Ｏ−ベンジル、−ＣＨ_２Ｃ（Ｏ）−Ｎ（ＣＨ_３）_２、および

-C _{1 to 6} alkylene -C ^{(O) R 31,} for _{example, -CH 2 C (O) OCH} 3, -CH 2 C (O) O- _{benzyl, -CH 2 C (O) -N} (CH 3) ₂ and

−Ｃ_０〜６アルキレンモルホリニル、例えば、−（ＣＨ_２）_２−モルホリニルおよび−（ＣＨ_２）_３−モルホリニル：

—C _0-6 alkylenemorpholinyl, for example — (CH ₂ ) ₂ -morpholinyl and — (CH ₂ ) ₃ -morpholinyl:

−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル、例えば、−（ＣＨ_２）_２ＳＯ_２ＣＨ_３；

-C _{1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, _{e.g., - (CH 2) 2 SO} 2 CH 3;

から選択される。
Ｒ^１０部分は、
−Ｃ_１〜６アルキル、例えば、−ＣＨ_３および−ＣＨ_２ＣＨ_３；
−Ｏ−Ｃ_１〜６アルキル、例えば、−ＯＣＨ_３、−Ｏ−ＣＨ_２ＣＨ_３、および−Ｏ−ＣＨ（ＣＨ_３）_２；
−Ｃ_３〜７シクロアルキル、例えば、シクロペンチル）；
−Ｏ−Ｃ_３〜７シクロアルキル、例えば、−Ｏ−シクロプロピル、−Ｏ−シクロヘキシル、および−Ｏ−シクロペンチル；
フェニル；
−Ｏ−フェニル；
−ＮＲ^１２Ｒ^１３；
−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨ_２；
−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）Ｏ−Ｃ_１〜６アルキル、例えば、−ＣＨ［ＣＨ（ＣＨ_３）_２］−ＮＨＣ（Ｏ）ＯＣＨ_３；および
−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３
から選択される。
Ｒ^１２およびＲ^１３部分は、独立して、Ｈ、−Ｃ_１〜６アルキル（例えば、ＣＨ_３）、およびベンジルから選択される。あるいは、Ｒ^１２およびＲ^１３部分は、−（ＣＨ_２）_３〜６−、−Ｃ（Ｏ）−（ＣＨ_２）_３−、または−（ＣＨ_２）_２Ｏ（ＣＨ_２）_２−として一つになって、例えば、

Selected from.
R ¹⁰ part is
-C _{1 to 6} alkyl, e.g., -CH ₃ and _-CH 2 _CH 3;
_{-O-C 1 to 6} alkyl, for _{example, -OCH 3, -O-CH 2} CH 3, and _{-O-CH (CH 3) 2} ;
-C _3-7 cycloalkyl, eg cyclopentyl);
-O-C _3-7 cycloalkyl, such as -O-cyclopropyl, -O-cyclohexyl, and -O-cyclopentyl;
Phenyl;
-O-phenyl;
-NR ¹² R ^13;
_{-CH [CH (CH 3) 2} ] -NH 2;
_{-CH [CH (CH 3) 2} ] -NHC (O) O-C 1~6 alkyl, _{e.g., -CH [CH (CH 3)} 2] -NHC (O) OCH 3; and -CH _(NH 2) CH ₂ COOCH ₃
Selected from.
The R ¹² and R ¹³ moieties are independently selected from H, —C _1-6 alkyl (eg, CH ₃ ), and benzyl. Alternatively, the R ¹² and R ¹³ moieties are one as — (CH ₂ ) _3-6 —, —C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —. For example,

などの基を形成することもできる。
Ｒ^３１部分は、−Ｏ−Ｃ_１〜６アルキル、例えば、−ＯＣＨ_３、−Ｏ−ベンジル、および−ＮＲ^１２Ｒ^１３、例えば、−Ｎ（ＣＨ_３）_２および

It is also possible to form groups such as
The R ³¹ moiety is —O—C _1-6 alkyl, such as —OCH ₃ , —O-benzyl, and —NR ¹² R ¹³ , such as —N (CH ₃ ) ₂ and

などから選択される。
Ｒ^３２部分は、−Ｃ_１〜６アルキル（例えば、−ＣＨ_３および−Ｃ（ＣＨ_３）_３）または−Ｃ_０〜６アルキレン−Ｃ_６〜１０アリールである。

Etc. are selected.
The R ³² moiety is —C _1-6 alkyl (eg, —CH ₃ and —C (CH ₃ ) ₃ ) or —C _0-6 alkylene-C _6-10 aryl.

R ⁸ part is
H;
-OH;
-OC ^{(O) R 14,} for _{example, -OC (O) CH 3,} -OC (O) - phenyl, -OC (O) -OCH ₂ - phenyl, -OC (O) _-CH 2 O- phenyl, - OC (O) (NH ₂ ), and —OC (O) [N (CH ₃ ) ₂ ;
-CH ₂ COOH;
-O-benzyl;
Pyridyl; and —OC (S) NR ¹⁵ R ¹⁶ , for example, —OC (S) NH ₂ and —OC (S) N (CH ₃ ) _2.
Selected from.
R ¹⁴ moiety is
H;
-C _{1 to 6} alkyl, e.g., _-CH 3;
_-C6-10 aryl, such as phenyl;
-OCH ₂ -C _{6 to 10} aryl, for example, -OCH ₂ - phenyl;
-CH _{2 O-C} 6~10 aryl, for example, _-CH 2 O-phenyl; and -NR ¹⁵ R ^16, for example, -NH ₂ and N _{(CH 3) 2}
Selected from.
The R ¹⁵ and R ¹⁶ moieties are independently selected from H and —C _1-4 alkyl.

R ⁹ is a moiety selected from H, —C _1-6 alkyl (eg, —CH ₃ ), and —C (O) R ¹⁷ (eg, —C (O) H). The R ¹⁷ moiety is H, —C _1-6 alkyl (eg, —CH ₂ CH ₃ ), —C _3-7 cycloalkyl (eg, cyclopropyl), —C _6-10 aryl (eg, phenyl), and Selected from —C _1-9 heteroaryl (eg pyridine).

In addition, each alkyl group in R ¹ is optionally substituted with 1 to 8 fluoro atoms. For example, when R ¹ is —OR ⁷ and R ⁷ is —C _1-8 alkyl, R ¹ is also —OCH (CH ₃ ) CF ₃ , —OCH ₂ CF ₂ CF ₃ , —OCH (CF _{3) 2,} may be a group such as _{-O (CH 2) 2 CF 3} , -OCH (CH 2 F) 2, -OC (CF 3) 2 CH 3, and -OCH _(CH 3) _CF 2 CF ₃ .

In one embodiment, R ¹ is selected from —OR ⁷ and R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylene mole. _{Horiniru, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, and

から選択され、Ｒ^１０は、−Ｏ−Ｃ_３〜７シクロアルキル、および−ＮＲ^８Ｒ^９であり、Ｒ^８はＨであり、Ｒ^９はＨである。別の実施形態では、これらの化合物は、式ＩＩＩを有する。

R ¹⁰ is —O—C _3-7 cycloalkyl, and —NR ⁸ R ⁹ , R ⁸ is H, and R ⁹ is H. In another embodiment, these compounds have Formula III.

In one embodiment, R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, R ⁸ is H or —OH, and R ⁹ is H. In another embodiment, these compounds have Formula III.

In another embodiment, R ¹ is —OR ⁷ and R ⁷ is —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9. Heteroaryl, —C _3-7 cycloalkyl, — [(CH ₂ ) ₂ O] _1-3 CH ₃ , —C _1-6 alkylene-OC (O) R ¹⁰ , —C _1-6 alkylene-NR ¹² R ^13, _{-C 1 to 6} alkylene _{^{-C (O) R 31, -C}} 0~6 alkylene _{morpholinylcarbonyl; -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl;

から選択される。
さらに別の実施形態では、Ｒ^１は−ＮＲ^８Ｒ^９であり、Ｒ^８は、−ＯＣ（Ｏ）Ｒ^１４、−ＣＨ_２ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^９はＨである。さらに別の実施形態では、Ｒ^１は−ＮＲ^８Ｒ^９であり、Ｒ^８はＨまたは−ＯＨであり、Ｒ^９は−Ｃ_１〜６アルキルまたは−Ｃ（Ｏ）Ｒ^１７である。さらに別の実施形態では、Ｒ^１は−ＮＲ^８Ｒ^９であり、Ｒ^８は、−ＯＣ（Ｏ）Ｒ^１４、−ＣＨ_２ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^９は−Ｃ_１〜６アルキルまたは−Ｃ（Ｏ）Ｒ^１７である。別の実施形態ではこれらの化合物は式ＩＩＩを有する。本発明の一態様では、これらの化合物に、プロドラッグとして、または本明細書中に記載されている合成手順の中間体としての特定の有用性を見出すことができる。例えば、一実施形態では、Ｒ^１は、−ＯＲ^７であり、Ｒ^７は−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^１０、例えば−Ｏ−ＣＨ（ＣＨ_３）ＯＣ（Ｏ）−Ｏ−シクロヘキシルなどであり、

Selected from.
In yet another embodiment, R ¹ is —NR ⁸ R ⁹ and R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ^15. Selected from R ¹⁶ and R ⁹ is H. In yet another embodiment, R ¹ is —NR ⁸ R ⁹ , R ⁸ is H or —OH, and R ⁹ is —C _1-6 alkyl or —C (O) R ¹⁷ . In yet another embodiment, R ¹ is —NR ⁸ R ⁹ and R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ^15. Selected from R ¹⁶ , R ⁹ is —C _1-6 alkyl or —C (O) R ¹⁷ . In another embodiment, these compounds have Formula III. In one aspect of the invention, these compounds may find particular utility as prodrugs or as intermediates in the synthetic procedures described herein. For example, in one embodiment, R ¹ is —OR ⁷ and R ⁷ is —C _1-6 alkylene-OC (O) R ¹⁰ , eg, —O—CH (CH ₃ ) OC (O) —O—. Cyclohexyl, etc.

とすることにより、化合物をシレキセチルエステルとするか、またはＲ^１は、−ＯＲ^７であり、Ｒ^７は、−Ｃ_０〜６アルキレンモルホリニル、例えば−Ｏ−（ＣＨ_２）_２−モルホリニルなどであり、

To make the compound a cilexetil ester, or R ¹ is —OR ⁷ and R ⁷ is —C _0-6 alkylenemorpholinyl, such as —O— (CH ₂ ) ₂ —. Such as morpholinyl,

とすることにより、化合物を２−モルホリノエチルもしくはモフェチルエステルとするか、またはＲ^１は、−ＯＲ^７であり、Ｒ^７は、

Or the compound is 2-morpholinoethyl or mofetil ester, or R ¹ is —OR ⁷ and R ⁷ is

であり、例えば−Ｏ−ＣＨ_２−５−メチル−［１，３］ジオキソール−２−オンであり、

, And the example _-O-CH 2-5-methyl - a [1,3] dioxol-2-one,

とすることにより、化合物をメドキソミルエステルとする。

To make the compound medoxomil ester.

R ² is H or —P (O) (OH) ₂ . R ² can also be taken together with R ⁷ to form —CR ¹⁸ R ¹⁹ —, or can be taken together with R ⁸ to form —C (O) —. R ¹⁸ and R ¹⁹ are independently selected from H, —C _1-6 alkyl, and —O—C _3-7 cycloalkyl, or R ¹⁸ and R ¹⁹ together are O can be formed. In one embodiment, R ² is H. In another embodiment, the compound has Formula III.

R ² is ^-CR 18 ^{R 19} taken together with ^{R 7} - when forming the present embodiment,

と描写することができ、Ｒ^１８およびＲ^１９が一緒になって＝Ｏを形成する場合、本実施形態は、

And when R ¹⁸ and R ¹⁹ together form ═O, this embodiment is

と描写することができる。

Can be described.

When R ² together with R ⁸ forms —C (O) —, this embodiment is

と描写することができる。

Can be described.

In one aspect of the invention, these compounds may find particular utility as prodrugs or as intermediates in the synthetic procedures described herein. In another embodiment, these compounds have Formula III. Moreover, the usefulness as a prodrug can be found in the compound in which R ² is —P (O) (OH) ₂ .

The “X” moiety is —C _1-9 heteroaryl and the point of attachment is at the position of any available carbon or nitrogen ring atom. It should be noted that in some embodiments, R ³ and / or R ⁴ may not be present. When present, R ³ is on any available carbon atom. When present, R ⁴ is on any available carbon or nitrogen atom. Exemplary —C _1-9 heteroaryl rings include, by way of example and not limitation, the following:
Pyrazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
イミダゾール環（例えば

),
Imidazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
トリアゾール環（１，２，３−トリアゾール（例えば

),
Triazole ring (1,2,3-triazole (eg

である）ならびに１，２，４−トリアゾール（例えば

As well as 1,2,4-triazole (e.g.

である）が挙げられる）、
ベンゾトリアゾール環（例えば

Is)),
Benzotriazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
フラン環（

),
Franc ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
ピロール環（

),
Pyrrole ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
テトラゾール環（例えば

),
Tetrazole ring (eg

である）、
ピラジン環（

),
Pyrazine ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
チオフェン環（

),
Thiophene ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
オキサゾール環（

),
Oxazole ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
イソオキサゾール環（

),
Isoxazole ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
チアゾール環（

),
Thiazole ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
イソチアゾール環（

),
Isothiazole ring (

）、
オキサジアゾール環（［１，２，４］オキサジアゾール（例えば

),
Oxadiazole ring ([1,2,4] oxadiazole (for example

である）、ならびに［１，２，３］オキサジアゾール（例えば

As well as [1,2,3] oxadiazole (e.g.

である）、および［１，３，４］オキサジアゾール（

And [1,3,4] oxadiazole (

）が挙げられる）、
チアジアゾール環（［１，２，４］チアジアゾール（例えば

))
Thiadiazole ring ([1,2,4] thiadiazole (eg

である）、ならびに［１，２，３］チアジアゾール（例えば

As well as [1,2,3] thiadiazole (eg

である）、および［１，３，４］チアジアゾール（

And [1,3,4] thiadiazole (

）が挙げられる）、
ピリダジン環（

))
Pyridazine ring (

である）、
ピリジン環（

),
Pyridine ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
ピリミジン環（

),
Pyrimidine ring (

であり、この具体例として、

As a concrete example of this,

が挙げられる）、
ピラン環（例えば

),
Pyran ring (eg

である）、
ベンゾイミダゾール環（例えば

),
Benzimidazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
ベンゾオキサゾール環（例えば

),
Benzoxazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
ベンゾチアゾール環（例えば

),
Benzothiazole ring (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、
ピリジルイミダゾール環（例えば

),
Pyridylimidazole rings (eg

であり、これらの具体例として、

And as a concrete example of these,

が挙げられる）、ならびに
ピリジルトリアゾール環（例えば

As well as pyridyltriazole rings (e.g.

が挙げられ、
これらの具体例として、

Are mentioned,
As specific examples of these,

が挙げられる）。

For example).

  In one particular embodiment, X is pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridazine, pyridine, Selected from pyrimidine, pyran, benzimidazole, benzoxazole, benzothiazole, pyridylimidazole, and pyridyltriazole.

Some —C _1-9 heteroaryl rings can exist in tautomeric forms, such tautomeric forms being part of the present invention and referred to as “heteroaryl” It should be understood that the term is encompassed. Thus, when a compound is depicted with a —C _1-9 heteroaryl ring, the compound can also exist in a tautomeric form, and vice versa, and both forms are encompassed by the present invention. I want you to understand.

１つの特定の実施形態では、Ｘは、ピラゾール、トリアゾール、ベンゾトリアゾール、フラン、テトラゾール、ピラジン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、オキサジアゾール、ピリダジン、ピリジン、ピリミジン、ベンゾオキサゾール、ピリジルイミダゾール、およびピリジルトリアゾールから選択される。別の実施形態では、Ｘは、ピラゾール、トリアゾール、ベンゾトリアゾール、イソオキサゾール、ピリダジン、ピリミジン、およびピリジルトリアゾールから選択される。さらなる別の実施形態では、Ｘはイソオキサゾールであり、１つの特定の実施形態では、式ＩＩＩ：

In one particular embodiment, X is pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and Selected from pyridyltriazole. In another embodiment, X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole. In yet another embodiment, X is isoxazole, and in one particular embodiment is Formula III:

（式中、Ｒ^１〜Ｒ^６、ａ、およびｂは式Ｉに対して定義された通りである）を有する。さらに別の実施形態では、本発明の化合物は、式ＩＩＩａ：

Wherein R ^{1 to} R ⁶ , a, and b are as defined for Formula I. In yet another embodiment, the compound of the invention is of formula IIIa:

（式中、Ｒ^１、Ｒ^５、Ｒ^６、ａ、およびｂは式Ｉに対して定義された通りである）を有する。さらなる別の実施形態では、本発明の化合物は、式ＩＩＩｂ：

Wherein R ¹ , R ⁵ , R ⁶ , a, and b are as defined for Formula I. In yet another embodiment, the compound of the invention has formula IIIb:

（式中、Ｒ^１、Ｒ^５、Ｒ^６、ａ、およびｂは、式Ｉに対して定義された通りである）を有する。

Wherein R ¹ , R ⁵ , R ⁶ , a, and b are as defined for Formula I.

The R ³ moiety may not be present. When present, R ³ is bonded to a carbon atom in the “X” group;
H;
Halo, such as chloro and fluoro;
-C _{0 to 5} alkylene -OH, for _{example, -OH, -CH 2 OH, -CH} (OH) CH 3, and _{-C (CH} 3) 2 -OH;
-NH _2;
-C _{1 to 6} alkyl, _{e.g., -CH 3, - (CH 2} ) 2 CH 3, -CH (CH 3) 2, and _{- (CH 2) 3 -CH 3} ;
-CF _{3;
-C3-7cycloalkyl} , such as cyclopropyl and cyclohexyl;
-C _{0 to 2} alkylene _{-O-C 1 to 6} alkyl, for _{example, -OCH 3, -OCH 2 CH 3} , -CH 2 -OCH 3, and _{- (CH 2) 2 -OCH 3} ;
-C ^{(O) R 20,} for example, -C (O) H and -C (O) _CH 3;
—C _0-1 alkylene-COOR ²¹ , for example, —COOH, —CH ₂ —COOH, —C (O) O—CH ₂ CH ₃ , —C (O) O— (CH ₂ ) ₂ OCH ₃ , —C (O) O—CH ₂ OC (O) CH ₃ , —CH ₂ —C (O) O—CH ₂ OC (O) CH ₃ , —C (O) O—CH ₂ OC (O) O—CH ₃ , —CH ₂ —C (O) O—CH ₂ OC (O) O—CH ₃ , —C (O) O—CH (CH ₃ ) OC (O) O—CH ₂ CH ₃ , —C (O) _{O-CH (CH 3) OC} (O) O-CH (CH 3) 2, -C (O) O-CH 2 CH (CH 3) OC (O) - cyclopentyl, -C (O) O-CH 2 OC (O) _{O-cyclopropyl, -C (O) O-CH} (CH 3) -OC (O) -O- _{cyclohexyl, -C (O) O-CH} 2 O (O) _{O-cyclopentyl, -C (O) O-CH} 2 CH (CH 3) OC (O) - _{phenyl, -C (O) O-CH} 2 OC (O) O- phenyl, -C (O) O-CH ₂ - pyridine, -C (O) O-CH 2 - _{pyrrolidine, -C (O) O- (CH} 2) 2 - _{morpholinyl, -C (O) O- (CH} 2) 3 - morpholinyl, and _{-C (O) O- (CH 2} ) 2 -SO 2 -CH 3;
^{-C (O) NR 22 R 23} , for _{example, -C (O) NH 2,} -C (O) NHCH 3, -C (O) N (CH 3) 2, -C (O) NH- (CH 2 ) ₂ CH ₃ , —C (O) NH—CH ₂ COOH, —C (O) NH— (CH ₂ ) ₂ —OH, —C (O) NH— (CH ₂ ) ₂ —N (CH ₃ ) ₂ , -C (O) NH- _{cyclopropyl, -C (O) NH- (CH} 2) 2 - _{imidazolyl, -C (O) N (CH} 3) -CH 2 CH (CH 3) 2, and -C ( O) N (CH ₃ ) [(CH ₂ ) ₂ OCH ₃ ];
—NHC (O) R ²⁴ , for example, —NHC (O) —CH ₂ CH ₃ , —NHC (O) — (CH ₂ ) ₃ CH ₃ , —NHC (O) O—CH ₂ CH ₃ , —NHC ( _{O) -CH 2 -OCH 3, -NHC} (O) -2- methoxyphenyl, -NHC (O) -2- chlorophenyl, and -NHC (O) -2- pyridine;
= O;
-NO _{2;
-C (CH 3) = N (} OH);
Phenyl optionally substituted with one or two groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl (eg, phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-hydroxyphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-NHC (O) CH 3 - phenyl 4-chlorophenyl, 4-fluorophenyl, 4-methoxyphenyl, 4-biphenyl, 2,5-dichlorophenyl, 2,5-dimethoxyphenyl, 2,4-dichlorophenyl, 2-methoxy, 5-fluorophenyl, and 3, 4-dichlorophenyl);
Naphthalenyl;
Pyridinyl;
Pyrazinyl;
Pyrazolyl optionally substituted with methyl;
Thiophenyl optionally substituted with methyl or halo (eg, chloro);
Furanyl; and —CH ₂ -morpholinyl.

The R ²⁰ moiety is selected from H and —C _1-6 alkyl (eg, —CH ₃ ). R ²¹ moiety is
H;
-C _{1 to 6} alkyl, e.g., -CH ₃ and _-CH 2 _CH 3;
-C _{1 to 3} alkylene _{-C 6 to 10} aryl;
-C _{1 to 3} alkylene _{-C 1 to 9} heteroaryl, for example, -CH ₂ - pyridine;
_{-C3-7cycloalkyl} ;
_{- [(CH 2) 2 O} ] 1~3 CH 3, for _{example, - (CH 2) 2 OCH} 3;
-C _{1 to 6} alkylene -OC ^{(O) R 25,} for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) O-CH 3, -CH 2 OC (O) O-CH 3, _{-CH (CH 3) OC (O} ) O-CH 2 CH 3, -CH (CH 3) OC (O) O-CH (CH 3) 2, -CH 2 CH (CH 3) OC (O) - cyclopentyl , _-CH 2 OC (O) O- _{cyclopropyl, -CH (CH 3) -OC (} O) -O- _cyclohexyl, -CH 2 OC (O) O- _{cyclopentyl, -CH 2 CH (CH 3)} OC ( O) - phenyl, and _-CH 2 OC (O) O- phenyl;
-C _{1 to 6} alkylene ^-NR 27 ^{R 28,} for example, -CH ₂ - pyrrolidine;
_{-C1-6alkylene-} C (O) ^R33 ;
—C _0-6 alkylenemorpholinyl, for example — (CH ₂ ) ₂ -morpholinyl and — (CH ₂ ) ₃ -morpholinyl:

−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル、例えば、−（ＣＨ_２）_２−ＳＯ_２−ＣＨ_３；

-C _{1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, _{e.g., - (CH 2) 2 -SO} 2 -CH 3;

から選択される。

Selected from.

R ²² and R ²³ moieties are independently H;
-C _{1 to 6} alkyl, e.g., -CH ₃ and _{- (CH 2) 2 CH 3} ;
-CH ₂ COOH;
- _{(CH 2) 2} OH;
_{- (CH 2) 2 OCH 3} ;
_{- (CH 2) 2 SO 2} NH 2;
_{- (CH 2) 2 N (} CH 3) 2;
-C _{0 to 1} alkylene _{-C 3 to 7} cycloalkyl, e.g., cyclopropyl, and -CH ₂ - cyclopropyl; and - _{(CH 2) 2} - is selected from imidazolyl.

R ²² and R ²³ together are optionally substituted with halo, —OH, —COOH, or —CONH ₂ and optionally containing an oxygen atom in the ring, saturated or Partially unsaturated —C _3-5 heterocycles may be formed. Saturated -C _3-5 heterocycles include azetidine, pyrrolidine, piperidine and morpholine, and thus as typical R ³ groups:

が挙げられる。

Is mentioned.

Partially unsaturated —C _3-5 heterocycles include 2,5-dihydro-1H-pyrrole, and thus, as a typical R ³ group,

が挙げられる。

Is mentioned.

R ²⁴ moiety is
-C _{1 to 6} alkyl, e.g., _-CH 2 CH ₃ and _{- (CH 2) 3 CH 3} ;
-C _{0 to 1} alkylene _{-O-C 1 to 6} alkyl, e.g., _-O-CH 2 _{CH 3} and _-CH 2 -OCH _3;
Selected from phenyl optionally substituted with halo or —OCH ₃ , eg, -2chlorophenyl or -2-methoxyphenyl; and —C _1-9 heteroaryl, eg, 2-pyridine.

R ²⁵ is
-C _{1 to 6} alkyl, _{e.g., -CH 3, -CH 2 CH 3} , and _{- (CH 2) 3 CH 3} ;
_{-O-C 1 to 6} alkyl, for _{example, -OCH 3, -OCH 2 CH 3} , and -OCH _{(CH 3)} 2;
_{-C3-7cycloalkyl} , such as cyclopentyl;
-O-C _3-7 cycloalkyl, such as -O-cyclopropyl, -O-cyclopentyl, and -O-cyclohexyl;
Phenyl;
-O-phenyl;
-NR ²⁷ R ^28;
_{-CH [CH (CH 3) 2} ] -NH 2;
_{-CH [CH (CH 3) 2} ] -NHC (O) O-C 1~6 alkyl, _{e.g., -CH [CH (CH 3)} 2] -NHC (O) OCH 3; and -CH _(NH 2) CH ₂ COOCH ₃
Selected from.

R ²⁷ and R ²⁸ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ²⁷ and R ²⁸ are — (CH ₂ ) _3-6 —, —C (O ) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, wherein R ³³ is —O—C _1-6 alkyl, —O-benzyl, and —NR. Selected from ²⁷ R ²⁸ , R ³⁴ is —C _1-6 alkyl (eg, —CH ₃ and —C (CH ₃ ) ₃ ) or —C _0-6 alkylene-C _6-10 aryl.

In addition, each alkyl group in R ³ is optionally substituted with 1 to 8 fluoro atoms. For example, when R ³ is —C _0-1 alkylene-COOR ²¹ and R ²¹ is —C _1-6 alkyl, R ³ is also —COOCH (CH ₃ ) CF ₃ , —COOCH ₂ CF ₂ CF ₃ , —COOCH (CF ₃ ) ₂ , —COO (CH ₂ ) ₂ CF ₃ , —COOCH (CH ₂ F) ₂ , —COOC (CF ₃ ) ₂ CH ₃ , and —COOCH (CH ₃ ) CF ₂ CF ₃ It can also be a group such as

In one embodiment, R ³ is absent or H; halo; —C _0-5 alkylene-OH; —NH ₂ ; —C _1-6 alkyl; —CF ₃ ; —C _3-7 cycloalkyl; C _{0 to 2} alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; ═O; —C (CH ₃ ) ═N (OH); one or two groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl Optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl substituted with methyl; thiophenyl substituted with methyl or halo; furanyl; and —CH ₂ -morpholinyl R ²⁰ is —C _1-6 alkyl, R ²¹ is selected from H and —C _1-6 alkyl, R ²² is selected from H and —C _1-6 alkyl, and R ²³ is , H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _3-7 Selected from cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ^{23 taken} together are azetidine, pyrrolidine, piperidine or morpholine, all of which are —OH or —CONH ₂ . substituted are) to form an ^{optionally, R 24} _{is, -C 1 to 6 alkyl;} phenyl substituted with halo or -OCH _{3; -C 0 to 1} alkylene _{-O-C 1 to 6} alkyl And it is selected from pyridine. In other embodiments, these compounds have Formula III.

In one embodiment, R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl. -C _0-2 alkylene-O-C _1-6 alkyl; -C (O) R ²⁰ ; -C _0-1 alkylene-COOR ²¹ ; -C (O) NR ²² R ²³ ; -NHC (O) R _{^{24; = O; -NO 2;}} -C (CH 3) = N (OH); _{halo, -OH, -CF 3, -OCH 3} , is independently selected from -NHC (O) CH _3, and phenyl Phenyl optionally substituted with one or two groups; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl optionally substituted with methyl; thiophenyl optionally substituted with methyl or halo; furanyl ; Rabi and —CH ₂ -morpholinyl are selected and R ²¹ is H. In other embodiments, these compounds have Formula III.

In another embodiment, R ³ is —C _0-1 alkylene-COOR ²¹ , wherein R ²¹ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _{1— 3} alkylene _{-C 1 to 9 heteroaryl, -C 3 to 7 cycloalkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene ^{-OC (O) R 25; -C} 1 ₆ alkylene ^-NR 27 ^R _{28, -C 1~6} alkylene _{^{-C (O) R 33, -C}} 0~6 alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

から選択される。

Selected from.

  In one aspect of the invention, these compounds may find particular utility as prodrugs or as intermediates in the synthetic procedures described herein. In other embodiments, these compounds have Formula III.

The R ⁴ moiety may not be present. When present, R ⁴ is bonded to a carbon or nitrogen atom in the “X” group;
H;
-OH;
-C _{1 to 6} alkyl, e.g., _-CH 3;
-C _{1 to 2} alkylene -COOR ^35, for _example, -CH 2 COOH and _{- (CH} 2) 2 -COOH;
^{_{-CH 2 OC (O) CH (}} R 36) NH 2, for _{example, -CH 2 OC (O) CH} [CH (CH 3) 2] NH 2;
^{_{-OCH 2 OC (O) CH (}} R 36) NH 2, for _{example, -OCH 2 OC (O) CH} [CH (CH 3) 2] NH 2;
_{-OCH 2 OC (O) CH 3} ;
_{-CH 2 OP (O) (OH} ) 2;
_{-CH 2 CH (OH) CH 2} OH;
_{-CH [CH (CH 3) 2} ] -NHC (O) O-C 1~6 alkyl;
Pyridinyl; and phenyl or benzyl optionally substituted with one or more groups selected from halo, —COOR ³⁵ , —OCH ₃ , —OCF ₃ , and —SCF ₃ (eg, 4-chlorophenyl, 3-methoxyphenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-chloro, 5-fluorophenyl, 3-trifluoromethoxy, 4-chlorophenyl, 3-trifluoromethylsulfanyl, 4-chlorophenyl, 2,6 -Difluoro, 4-chlorophenyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-carboxybenzyl, 4-carboxybenzyl, 3-methoxybenzyl, 2-chloro, 5-fluorobenzyl, 3-chloro, 5-fluorobenzyl, 2-fluoro, 4- Lorobenzyl, 3-chloro, 4-fluorobenzyl, 3-OCF3, 4-chlorobenzyl, 3-SCF3, 4-chlorobenzyl, 2,6-difluoro, 3-chlorobenzyl, 2,6-difluoro, 4-chlorobenzyl , And 2,3,5,6-tetrafluoro, 4-methoxybenzyl)
Selected from.

R ³⁵ moiety is
H;
-C _{1 to 6} alkyl, e.g., -CH ₃ and _-CH 2 _CH 3;
-C _{1 to 3} alkylene _{-C 6 to 10} aryl;
-C _{1 to 3} alkylene _{-C 1 to 9} heteroaryl, for example, -CH ₂ - pyridine;
_{-C3-7cycloalkyl} ;
_{- [(CH 2) 2 O} ] 1~3 CH 3, for _{example, - (CH 2) 2 OCH} 3;
-C _{1 to 6} alkylene -OC ^{(O) R 25,} for _{example, -CH 2 OC (O) CH} 3, -CH 2 OC (O) O-CH 3, -CH 2 OC (O) O-CH 3, _{-CH (CH 3) OC (O} ) O-CH 2 CH 3, -CH (CH 3) OC (O) O-CH (CH 3) 2, -CH 2 CH (CH 3) OC (O) - cyclopentyl , _-CH 2 OC (O) O- _{cyclopropyl, -CH (CH 3) -OC (} O) -O- _cyclohexyl, -CH 2 OC (O) O- _{cyclopentyl, -CH 2 CH (CH 3)} OC ( O) - phenyl, and _-CH 2 OC (O) O- phenyl;
-C _{1 to 6} alkylene ^-NR 27 ^{R 28,} for example, -CH ₂ - pyrrolidine;
_{-C1-6alkylene-} C (O) ^R33 ;
—C _0-6 alkylenemorpholinyl, for example — (CH ₂ ) ₂ -morpholinyl and — (CH ₂ ) ₃ -morpholinyl:

−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル、例えば、−（ＣＨ_２）_２−ＳＯ_２−ＣＨ_３；

-C _{1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, _{e.g., - (CH 2) 2 -SO} 2 -CH 3;

から選択される。

Selected from.

The R ²⁵ , R ²⁷ , R ²⁸ , R ³³ , and R ³⁴ moieties are defined above. The R ³⁶ moiety is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl.

In addition, each alkyl group in R ⁴ is optionally substituted with 1 to 8 fluoro atoms. For example, when R ⁴ is —C _1-2 alkylene-COOR ³⁵ and R ³⁵ is —C _1-6 alkyl, R ⁴ is also —COOCH (CH ₃ ) CF _3, —COOCH ₂ CF _{2. CF 3, -COOCH (CF 3)} 2, -COO (CH 2) 2 CF 3, -COOCH (CH 2 F) 2, -COOC (CF 3) 2 CH 3, and -COOCH _(CH 3) _CF 2 _CF It can be a group such as ₃ .

The R ⁴ moiety can also be taken together with R ³ to form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2- . For purposes of illustration only, these embodiments are depicted below and X is pyrazole. It should be understood that other X groups can also be used.

別の特定の実施形態では、Ｒ^４は存在しないか、またはＨ；−ＯＨ；−Ｃ_１〜６アルキル；−Ｃ_１〜２アルキレン−ＣＯＯＲ^３５；−ＣＨ_２ＯＣ（Ｏ）ＣＨ（Ｒ^３６）ＮＨ_２；−ＣＨ_２ＣＨ（ＯＨ）ＣＨ_２ＯＨ；ピリジニル；１つのハロ基で必要に応じて置換されているフェニル；ならびにハロ、−ＣＯＯＨ、−ＯＣＨ_３、−ＯＣＦ_３、および−ＳＣＦ_３から選択される１つもしくは複数の基で必要に応じて置換されているベンジルから選択され、Ｒ^３５はＨであり、Ｒ^３６は−ＣＨ（ＣＨ_３）_２であるか、あるいはＲ^３およびＲ^４は、一緒になって、−フェニレン−Ｏ−（ＣＨ_２）_１〜３−または−フェニレン−Ｏ−ＣＨ_２−ＣＨＯＨ−ＣＨ_２−を形成する。他の実施形態ではこれらの化合物は、式ＩＩＩを有する。

In another specific embodiment, R ⁴ is absent or H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ OC (O) CH (R ³⁶ ) _{NH 2; -CH 2 CH (OH} ) CH 2 OH; pyridinyl; one phenyl are optionally substituted with halo groups; and _{halo, -COOH, -OCH 3, -OCF 3} , and from -SCF ₃ Selected from benzyl optionally substituted with one or more selected groups, R ³⁵ is H and R ³⁶ is —CH (CH ₃ ) ₂ , or R ³ and R ⁴ together, - phenylene -O- _{(CH 2)} 1~3 - or - phenylene _{-O-CH 2 -CHOH-CH 2} - to form a. In other embodiments, these compounds have Formula III.

In one embodiment, R ⁴ is absent or H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ , _{-CH 2 CH (OH) CH 2} OH; pyridinyl; and _{^{halo, -COOR 35, -OCH 3, -OCF}} 3, and one or optionally substituted with a plurality of groups selected from -SCF ₃ Selected from phenyl or benzyl, R ³⁵ is H; In other embodiments, these compounds have Formula III.

In another embodiment, R ⁴ is —OCH ₂ OC (O) CH ₃ ; —CH ₂ OP (O) (OH) ₂ ; —C _1-2 alkylene-COOR ³⁵ ; and at least one —COOR ³⁵ group. Selected from phenyl or benzyl substituted with R ³⁵ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, -C _{3 to 7 cycloalkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene _{^{-OC (O) R 25; -C}} 1~6 alkylene ^-NR 27 ^{R 28,} - C _1-6 alkylene-C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

から選択される。

Selected from.

  In one aspect of the invention, these compounds may find particular utility as prodrugs or as intermediates in the synthetic procedures described herein. In other embodiments, these compounds have Formula III.

The numbering for the R ⁵ and R ⁶ groups is as follows:

整数「ａ」は０または１である。Ｒ^５部分は、存在する場合、ハロ、−ＣＨ_３、−ＣＦ_３、および−ＣＮから選択される。一実施形態では、ａは０である。別の実施形態では、ａは１であり、かつＲ^５はハロ、例えば３−クロロまたは３−フルオロなどである。整数「ｂ」は０であるか、または１〜３の整数である。Ｒ^６部分は、存在する場合、独立して、ハロ、−ＯＨ、−ＣＨ_３、−ＯＣＨ_３、および−ＣＦ_３から選択される。一実施形態では、ｂは０である。別の実施形態では、ｂは１であり、かつＲ^６は、Ｃｌ、Ｆ、−ＯＨ、−ＣＨ_３、−ＯＣＨ_３、および−ＣＦ_３から選択され、例えば２’−クロロ、３’−クロロ、２’−フルオロ、３’−フルオロ、２’−ヒドロキシ、３’−ヒドロキシ、３’−メチル、２’−メトキシ、または３’−トリフルオロメチルなどである。別の実施形態では、ｂは１であり、かつＲ^６はハロ、−ＣＨ_３、または−ＯＣＨ_３であり、例えば３’−クロロ、３’−メチル、または２’−メトキシなどである。一実施形態では、ｂは２であり、かつＲ^６は２’−フルオロ−５’−クロロ、２’，５’−ジクロロ、２’，５’−ジフルオロ、２’−メチル−５’−クロロ、３’−フルオロ−５’−クロロ、３’−ヒドロキシ−５’−クロロ、３’，５’−ジクロロ、３’，５’−ジフルオロ、２’−メトキシ−５’−クロロ、２’−メトキシ−５’−フルオロ、２’−ヒドロキシ−５’−フルオロ、２’−フルオロ−３’−クロロ、２’−ヒドロキシ−５’−クロロ、または２’−ヒドロキシ−３’−クロロであり、別の実施形態では、ｂは２であり、かつ各Ｒ^６は、独立して、ハロ、例えば、２’−フルオロ−５’−クロロおよび２’，５’−ジクロロなどである。別の実施形態では、ｂは３であり、かつ各Ｒ^６は独立して、ハロまたは−ＣＨ_３、例えば２’−メチル−３’、５’−ジクロロまたは２’−フルオロ−３’−メチル−５’−クロロなどである。さらに別の実施形態では、ａは１であり、ｂは１であり、かつＲ^５およびＲ^６は独立して、ハロ、例えば、３−クロロおよび３’クロロである。他の実施形態ではこれらの化合物は、式ＩＩＩを有する。特に興味深いのは、式：

The integer “a” is 0 or 1. The R ⁵ moiety, when present, is selected from halo, —CH ₃ , —CF ₃ , and —CN. In one embodiment, a is 0. In another embodiment, a is 1 and R ⁵ is halo, such as 3-chloro or 3-fluoro. The integer “b” is 0 or an integer of 1 to 3. The R ⁶ moiety, when present, is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ . In one embodiment, b is 0. In another embodiment, b is 1 and R ⁶ is selected from Cl, F, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ , such as 2′-chloro, 3′-chloro. 2′-fluoro, 3′-fluoro, 2′-hydroxy, 3′-hydroxy, 3′-methyl, 2′-methoxy, 3′-trifluoromethyl and the like. In another embodiment, b is 1 and R ⁶ is halo, —CH ₃ , or —OCH ₃ , such as 3′-chloro, 3′-methyl, or 2′-methoxy. In one embodiment, b is 2 and R ⁶ is 2′-fluoro-5′-chloro, 2 ′, 5′-dichloro, 2 ′, 5′-difluoro, 2′-methyl-5′-chloro. 3'-fluoro-5'-chloro, 3'-hydroxy-5'-chloro, 3 ', 5'-dichloro, 3', 5'-difluoro, 2'-methoxy-5'-chloro, 2'- Methoxy-5′-fluoro, 2′-hydroxy-5′-fluoro, 2′-fluoro-3′-chloro, 2′-hydroxy-5′-chloro, or 2′-hydroxy-3′-chloro, In another embodiment, b is 2 and each R ⁶ is independently halo, such as 2′-fluoro-5′-chloro and 2 ′, 5′-dichloro. In another embodiment, b is 3 and each R ⁶ is independently halo or —CH ₃ , such as 2′-methyl-3 ′, 5′-dichloro or 2′-fluoro-3′-methyl. Such as -5'-chloro. In yet another embodiment, a is 1, b is 1, and R ⁵ and R ⁶ are independently halo, such as 3-chloro and 3 ′ chloro. In other embodiments, these compounds have Formula III. Of particular interest is the formula:

の化合物である。

It is this compound.

The methylene linker on biphenyl is optionally substituted with one or two —C _1-6 alkyl groups or cyclopropyl. For example, in one embodiment, the methylene linker on biphenyl is unsubstituted, and in another embodiment, the methylene linker on biphenyl is substituted with one —C _1-6 alkyl group (eg, —CH ₃ ). In yet another embodiment, the methylene linker on biphenyl is substituted with two —C _1-6 alkyl groups (eg, two —CH ₃ groups), and in another embodiment, on the biphenyl The methylene linker is substituted with a cyclopropyl group. Each of these embodiments is

と描写される。

It is described.

In another embodiment, R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene- SO ₂ -C _{1 to 6} alkyl, and

から選択され、
Ｒ^１０は、−Ｏ−Ｃ_３〜７シクロアルキルであり、Ｒ^８はＨであり、Ｒ^９はＨであり、Ｒ^２はＨであり、Ｒ^３は存在しないか、またはＨ；ハロ；−Ｃ_０〜５アルキレン−ＯＨ；−ＮＨ_２；−Ｃ_１〜６アルキル；−ＣＦ_３；−Ｃ_３〜７シクロアルキル；−Ｃ_０〜２アルキレン−Ｏ−Ｃ_１〜６アルキル；−Ｃ（Ｏ）Ｒ^２０；−Ｃ_０〜１アルキレン−ＣＯＯＲ^２１；−Ｃ（Ｏ）ＮＲ^２２Ｒ^２３；−ＮＨＣ（Ｏ）Ｒ^２４；＝Ｏ；−Ｃ（ＣＨ_３）＝Ｎ（ＯＨ）；ハロ、−ＯＨ、−ＣＦ_３、−ＯＣＨ_３、−ＮＨＣ（Ｏ）ＣＨ_３、およびフェニルから独立して選択される１もしくは２つの基で必要に応じて置換されているフェニル；ナフタレニル；ピリジニル；ピラジニル；メチルで置換されているピラゾリル；メチルもしくはハロで置換されているチオフェニル；フラニル；ならびに−ＣＨ_２−モルホリニルから選択され、Ｒ^２０は−Ｃ_１〜６アルキルであり、Ｒ^２１はＨまたは−Ｃ_１〜６アルキルであり、Ｒ^２２はＨまたは−Ｃ_１〜６アルキルであり、Ｒ^２３は、Ｈ、−Ｃ_１〜６アルキル、−ＣＨ_２ＣＯＯＨ、−（ＣＨ_２）_２ＯＨ、−（ＣＨ_２）_２ＯＣＨ_３、−（ＣＨ_２）_２Ｎ（ＣＨ_３）_２、−Ｃ_３〜７シクロアルキル、および−（ＣＨ_２）_２−イミダゾリルから選択されるか、またはＲ^２２およびＲ^２３は一緒になって、アゼチジン、ピロリジン、ピペリジンまたはモルホリン（これらはすべて、−ＯＨまたは−ＣＯＮＨ_２で必要に応じて置換されている）を形成し、Ｒ^２４は−Ｃ_１〜６アルキル；−Ｃ_０〜１アルキレン−Ｏ−Ｃ_１〜６アルキル；ハロまたは−ＯＣＨ_３で置換されているフェニルおよびピリジニルから選択され、Ｒ^４は存在しないか、またはＨ；−ＯＨ；−Ｃ_１〜６アルキル；−Ｃ_１〜２アルキレン−ＣＯＯＲ^３５；−ＣＨ_２ＯＣ（Ｏ）ＣＨ（Ｒ^３６）ＮＨ_２；−ＣＨ_２ＣＨ（ＯＨ）ＣＨ_２ＯＨ；ピリジニル；１つのハロ基で必要に応じて置換されているフェニル；ならびにハロ、−ＣＯＯＨ、−ＯＣＨ_３、−ＯＣＦ_３、および−ＳＣＦ_３から選択される１つもしくは複数の基で必要に応じて置換されているベンジルから選択され、Ｒ^３５はＨであり、Ｒ^３６は−ＣＨ（ＣＨ_３）_２であるか、あるいはＲ^３およびＲ^４は一緒になって、−フェニレン−Ｏ−（ＣＨ_２）_１〜３−または−フェニレン−Ｏ−ＣＨ_２−ＣＨＯＨ−ＣＨ_２−を形成し、ａは０であるか、またはａは１であり、かつＲ^５は３−クロロであり、ｂは０であるか、もしくはｂは１であり、かつＲ^６は３’−クロロ、３’−メチル、もしくは２’−メトキシであるか、またはｂは２であり、かつＲ^６は２’−フルオロ−５’−クロロ、２’，５’−ジクロロ、２’−メチル−５’−クロロ、もしくは３’−クロロ−５’−ヒドロキシであり、ビフェニル上のメチレンリンカーは、２つのメチル基で必要に応じて置換されている。一実施形態では、Ｘは、ピラゾール、トリアゾール、ベンゾトリアゾール、フラン、テトラゾール、ピラジン、チオフェン、オキサゾール、イソオキサゾール、チアゾール、オキサジアゾール、ピリダジン、ピリジン、ピリミジン、ベンゾオキサゾール、ピリジルイミダゾール、およびピリジルトリアゾールから選択される。

Selected from
R ¹⁰ is —O—C _3-7 cycloalkyl, R ⁸ is H, R ⁹ is H, R ² is H, R ³ is absent or H; halo; C _{0 to 5} alkylene _-OH; -NH 2; _{-C 1~6 alkyl;} -CF _{3; -C 3~7 cycloalkyl; -C 0 to 2} alkylene _{-O-C 1 to 6} alkyl; -C (O ) R ²⁰ ; —C _0-1 alkylene-COOR ²¹ ; —C (O) NR ²² R ²³ ; —NHC (O) R ²⁴ ; = O; —C (CH ₃ ) ═N (OH); halo, — _{OH, -CF 3, -OCH 3,} -NHC (O) CH 3, and phenyl which is optionally substituted with one or two groups independently selected from phenyl; naphthalenyl; pyridinyl; pyrazinyl; methyl Substituted with pyrazolyl; methyl or halo Thiophenyl substituted with: furanyl; and —CH ₂ -morpholinyl, R ²⁰ is —C _1-6 alkyl, R ²¹ is H or —C _1-6 alkyl, and R ²² is H or -C is _1-6 ^{alkyl, R 23} is, _{H, -C 1-6 alkyl, -CH 2 COOH, - (CH} 2) 2 OH, - (CH 2) 2 OCH 3, - (CH 2) 2 N (CH ₃ ) ₂ , —C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ²³ together are azetidine, pyrrolidine, piperidine or morpholine ( all of which are optionally substituted with -OH or -CONH ₂₎ is ^{formed, R 24} is _{-C 1 to 6 alkyl; -C 0 to 1} alkylene _{-O-C. 1 to} Alkyl; halo or is selected from phenyl and pyridinyl substituted with -OCH _3, or not ^{R 4} is present, or H; _{-OH; -C 1 to 6 alkyl; -C 1 to 2} alkylene -COOR ^35; - _{^{CH 2 OC (O) CH (}} R 36) NH 2; -CH 2 CH (OH) CH 2 OH; pyridinyl; one phenyl are optionally substituted with halo groups; and halo, -COOH, -OCH ₃ , —OCF ₃ , and benzyl optionally substituted with one or more groups selected from —SCF ₃ , R ³⁵ is H, and R ³⁶ is —CH (CH ₃ ). ₂ is either or ^{R 3} and ^{R 4} together, - phenylene -O- _{(CH 2) 1 to 3} - or - phenylene _{-O-CH 2 -CHOH-CH 2} - Formed, a is 0 or a is 1 and ^{R 5} is 3-chloro, or b is 0, or b is 1 and ^{R 6} is 3'-chloro, 3'-methyl or 2'-methoxy or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5' -Chloro, or 3'-chloro-5'-hydroxy, the methylene linker on biphenyl is optionally substituted with two methyl groups. In one embodiment, X is from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole. Selected.

In yet another embodiment, R ¹ is —OR ⁷ , R ² is H, X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole, and R ³ is H Halo; -C _0-5 alkylene-OH; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene-O-C _1-6 alkyl; -C (O ) R ²⁰ ; —C _0-1 alkylene-COOR ²¹ ; —C (O) NR ²² R ²³ ; —NHC (O) R ²⁴ ; = O; —C (CH ₃ ) ═N (OH); halo, — Phenyl optionally substituted with one or two groups independently selected from OH, and —OCH ₃ ; pyridinyl; pyrazinyl; and methyl or halo substituted thi R ⁴ is selected from Ophenyl, R ⁴ is H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ CH (OH) CH ₂ OH; pyridinyl; and one halo group Is optionally selected phenyl substituted or R ³ and R ^{4 taken} together form -phenylene-O— (CH ₂ ) _1-3 — and a is 0 Or a is 1, and R ⁵ is 3-chloro, b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2 ′. -Methoxy or b is 2 and R ⁶ is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro a ^{5'-hydroxy, R 20} is _{-C 1 to 6} alkyl, ^{R 2} Is ^{H, R 22} is selected from H and _{-C 1 to 6} ^{alkyl, R 23} _{is -C 1 to 6 alkyl, - (CH 2) 2 OCH} 3, and _{-C 3 to 7} cycloalkyl Or R ²² and R ²³ are taken together to form azetidine, pyrrolidine, or piperidine, all of which are optionally substituted with —OH or —CONH ₂ , and R ²⁴ Is phenyl substituted with halo or —OCH ₃ , R ³⁵ is H, the methylene linker on biphenyl is optionally substituted with two methyl groups, and R ⁷ is for formula I As defined.

  A particular group of compounds of formula I are disclosed in US Provisional Application No. 61 / 423,180, filed Dec. 15, 2010. This group includes compounds of formula II:

（式中、Ｒ^１は、−ＯＲ^７および−ＮＲ^８Ｒ^９から選択され、Ｒ^７は、Ｈ；−Ｃ_１〜６アルキル；−Ｃ_１〜３アルキレン−Ｃ_６〜１０アリール；−Ｃ_１〜３アルキレン−Ｃ_１〜９ヘテロアリール；−Ｃ_３〜７シクロアルキル；−（ＣＨ_２）_２ＯＣＨ_３；−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^１０；−ＣＨ_２−ピリジン；−ＣＨ_２−ピロリジン；−Ｃ_０〜６アルキレンモルホリン；−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル；

Wherein R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , wherein R ⁷ is H; —C _1-6 alkyl; —C _1-3 alkylene-C _6-10 aryl; —C _{1 to 3} alkylene _{-C 1 to 9 heteroaryl; -C 3 to 7} cycloalkyl _{;-( CH 2) 2 OCH 3;} -C 1~6 alkylene ^{-OC (O) R 10; -CH} 2 - pyridine; -CH ₂ -pyrrolidine; -C _0-6 alkylenemorpholine; -C _1-6 alkylene-SO ₂ -C _1-6 alkyl;

から選択され、Ｒ^１０は、−Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、−Ｃ_３〜７シクロアルキル、−Ｏ−Ｃ_３〜７シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ^１２Ｒ^１３、および−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３から選択され、Ｒ^１２およびＲ^１３は、独立して、Ｈ、−Ｃ_１〜６アルキル、およびベンジルから選択されるか、またはＲ^１２およびＲ^１３は、−（ＣＨ_２）_３〜６−として一つになり、Ｒ^８は、Ｈ；−ＯＨ；−ＯＣ（Ｏ）Ｒ^１４；−ＣＨ_２ＣＯＯＨ；−Ｏ−ベンジル；ピリジル；および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^１４は、Ｈ、−Ｃ_１〜６アルキル、−Ｃ_６〜１０アリール、−ＯＣＨ_２−Ｃ_６〜１０アリール、−ＣＨ_２Ｏ−Ｃ_６〜１０アリール、および−ＮＲ^１５Ｒ^１６から選択され、Ｒ^１５およびＲ^１６は、独立して、Ｈおよび−Ｃ_１〜４アルキルから選択され、Ｒ^９は、Ｈ；−Ｃ_１〜６アルキル；および−Ｃ（Ｏ）Ｒ^１７から選択され、Ｒ^１７はＨ；−Ｃ_１〜６アルキル；−Ｃ_３〜７シクロアルキル；−Ｃ_６〜１０アリール；および−Ｃ_１〜９ヘテロアリールから選択され、Ｒ^２はＨであるか、またはＲ^１と一緒になって、−ＯＣＨＲ^１８Ｒ^１９−または−ＮＨＣ（Ｏ）−を形成し、Ｒ^１８およびＲ^１９は、独立して、Ｈ、−Ｃ_１〜６アルキル、および−Ｏ−Ｃ_３〜７シクロアルキルから選択されるか、またはＲ^１８およびＲ^１９は一緒になって、＝Ｏを形成し、Ｘは−Ｃ_１〜９ヘテロアリールまたは部分的に不飽和の−Ｃ_３〜５ヘテロ環であり、Ｒ^３は存在しないか、またはＨ；ハロ；−Ｃ_０〜５アルキレン−ＯＨ；−ＮＨ_２；−Ｃ_１〜６アルキル；−Ｃ_３〜７シクロアルキル；−Ｃ_０〜１アルキレン−Ｏ−Ｃ_１〜６アルキル；−Ｃ（Ｏ）Ｒ^２０；−Ｃ_０〜１アルキレン−Ｃ（Ｏ）ＯＲ^２１；−Ｃ（Ｏ）ＮＲ^２２Ｒ^２３；−ＮＨＣ（Ｏ）Ｒ^２４；ハロ、−ＣＦ_３、−ＯＣＨ_３、−ＮＨＣ（Ｏ）ＣＨ_３、およびフェニルから選択される１つの基で必要に応じて置換されているフェニル；ナフチル（ｎａｐｔｈｙｌ）；ピリジン；ピラジン；メチルで必要に応じて置換されているピラゾール；メチルで必要に応じて置換されているチオフェン；ならびにフランから選択され、Ｒ^３は、存在する場合、炭素原子に結合しており、Ｒ^２０はＨおよび−Ｃ_１〜６アルキルから選択され、Ｒ^２１は、Ｈ；−Ｃ_１〜６アルキル；−Ｃ_１〜３アルキレン−Ｃ_６〜１０アリール；−Ｃ_１〜３アルキレン−Ｃ_１〜９ヘテロアリール；−Ｃ_３〜７シクロアルキル；−（ＣＨ_２）_２ＯＣＨ_３；−Ｃ_１〜６アルキレン−ＯＣ（Ｏ）Ｒ^２５；−ＣＨ_２−ピリジン；−ＣＨ_２−ピロリジン；−Ｃ_０〜６アルキレンモルホリン；−Ｃ_１〜６アルキレン−ＳＯ_２−Ｃ_１〜６アルキル；

R ¹⁰ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, — Selected from NR ¹² R ¹³ and —CH (NH ₂ ) CH ₂ COOCH ₃ , wherein R ¹² and R ¹³ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ¹² and R ¹³ are united as — (CH ₂ ) _3-6 —, and R ⁸ is H; —OH; —OC (O) R ¹⁴ ; —CH ₂ COOH; —O-benzyl; pyridyl; And —OC (S) NR ¹⁵ R ¹⁶ , wherein R ¹⁴ is H, —C _1-6 alkyl, —C _6-10 aryl, —OCH ₂ —C _6-10 aryl, —CH ₂ O—C. _6-10 aryl, and -NR ⁵ is selected from R ^{16, R 15} and ^{R 16} are independently selected from H and _{-C 1 to 4} alkyl, ^{R 9} is _{H; -C 1 to 6} alkyl; and -C (O) R is selected from ^{17, R 17} is _{H; -C 1 to 6 alkyl; -C 3 to 7 cycloalkyl; -C 6 to 10} aryl; is selected from and _{-C 1 to 9} heteroaryl, ^{R 2} is H Or together with R ¹ to form —OCHR ¹⁸ R ¹⁹ — or —NHC (O) —, wherein R ¹⁸ and R ¹⁹ are independently H, —C _1-6 alkyl, and — O—C _3-7 cycloalkyl is selected or R ¹⁸ and R ¹⁹ together form ═O, X is —C _1-9 heteroaryl or partially unsaturated —C _3-5 heteroaryl ring, or not ^{R 3} is present and also H; _{halo; -C 0 to 5} alkylene _-OH; -NH 2; _{-C 1~6 alkyl; -C 3 to 7 cycloalkyl; -C 0 to 1} alkylene _{-O-C 1 to 6} alkyl; -C ( _^O) R _{20; -C} 0~1 alkylene ^{-C (O) OR 21; -C} (O) NR 22 R 23; -NHC (O) R 24; _{halo, -CF 3, -OCH 3, -NHC} ( O) CH ₃ , and phenyl optionally substituted with one group selected from phenyl; naphthyl; pyridine; pyrazine; pyrazole optionally substituted with methyl; optionally with methyl Optionally substituted thiophene; and selected from furan, R ³ , if present, is attached to a carbon atom, R ²⁰ is selected from H and —C _1-6 alkyl, and R ²¹ is H ;- _{6alkyl; -C 1 to 3} alkylene _{-C 6 to 10 aryl; -C 1 to 3} alkylene _{-C 1 to 9 heteroaryl; -C 3 to 7} cycloalkyl _{;-( CH 2) 2 OCH 3;} - C _{1 to 6} alkylene ^{-OC (O) R 25; -CH} 2 - pyridine; -CH ₂ - _{pyrrolidine; -C Less than six} alkylene _{morpholine; -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl;

から選択され、
Ｒ^２５は−Ｃ_１〜６アルキル、−Ｏ−Ｃ_１〜６アルキル、−Ｃ_３〜７シクロアルキル、−Ｏ−Ｃ_３〜７シクロアルキル、フェニル、−Ｏ−フェニル、−ＮＲ^２７Ｒ^２８、および−ＣＨ（ＮＨ_２）ＣＨ_２ＣＯＯＣＨ_３から選択され、Ｒ^２７およびＲ^２８は、独立して、Ｈ、−Ｃ_１〜６アルキル、およびベンジルから選択されるか、またはＲ^２７およびＲ^２８は−（ＣＨ_２）_３〜６−として一つになり、Ｒ^２２およびＲ^２３は、独立して、Ｈ；−Ｃ_１〜６アルキル；−ＣＨ_２ＣＯＯＨ；−（ＣＨ_２）_２ＯＨ；−（ＣＨ_２）_２ＯＣＨ_３；−（ＣＨ_２）_２ＳＯ_２ＮＨ_２；−（ＣＨ_２）_２Ｎ（ＣＨ_３）_２；−Ｃ_３〜７シクロアルキル；および−（ＣＨ_２）_２−イミダゾールから選択されるか、またはＲ^２２およびＲ^２３は一緒になって、−ＯＨ、−ＣＯＯＨ、もしくは−ＣＯＮＨ_２で必要に応じて置換されており、環内に酸素原子を必要に応じて含有する飽和もしくは部分的に不飽和の−Ｃ_３〜５ヘテロ環を形成し、Ｒ^２４は、−Ｃ_１〜６アルキル；−Ｏ−Ｃ_１〜６アルキル；−ＣＨ_２−Ｏ−Ｃ_１〜６アルキル；−ＯＣＨ_３で置換されているフェニル；およびピリジンから選択され、Ｒ^４は、Ｈ；−Ｃ_１〜６アルキル；ハロ、−ＣＯＯＨ、−ＯＣＨ_３、−ＯＣＦ_３、および−ＳＣＦ_３から選択される１つまたは複数の基で置換されているフェニルまたはベンジルから選択され、Ｒ^４は、炭素または窒素原子に結合しており、ａは０または１であり、Ｒ^５はハロまたは−ＣＦ_３であり、ｂは０または１であり、Ｒ^６はハロである）または薬学的に許容されるその塩を含む。

Selected from
R ²⁵ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ²⁷ R ²⁸ , And —CH (NH ₂ ) CH ₂ COOCH ₃ and R ²⁷ and R ²⁸ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ²⁷ and R ²⁸ are _{- (CH 2)} 3~6 - become one ^{as, R 22} and ^{R 23} are independently, _{H; -C 1 to 6 alkyl; -CH 2 COOH ;-( CH 2)} 2 OH ;-( _{CH 2) 2 OCH 3 ;-( CH} 2) 2 SO 2 NH 2 ;-( CH 2) 2 N (CH 3) 2; -C 3~7 cycloalkyl; and - _{(CH 2) 2} - selected from imidazole or it is, or ^{R 22} Contact Fine ^{R 23} together, -OH, -COOH, or are optionally substituted with -CONH _2, a saturated or partially unsaturated optionally containing an oxygen atom in the ring - C _3-5 heterocycle is formed and R ²⁴ is substituted with —C _1-6 alkyl; —O—C _1-6 alkyl; —CH ₂ —O—C _1-6 alkyl; —OCH ₃ Selected from phenyl; and pyridine; R ⁴ is substituted with one or more groups selected from H; —C _1-6 alkyl; halo, —COOH, —OCH ₃ , —OCF ₃ , and —SCF ₃ R ⁴ is bonded to a carbon or nitrogen atom, a is 0 or 1, R ⁵ is halo or —CF ₃ , b is 0 or 1 , ^{R 6} is halo) also Including its pharmaceutically acceptable salts.

  Furthermore, particular compounds of formula I of interest include those described in the examples below, as well as pharmaceutically acceptable salts thereof.

General Synthetic Procedures Compounds of the present invention can be prepared using the following general methods, procedures described in the Examples, or by using other methods, reagents, and starting materials known to those skilled in the art. It can be prepared from readily available starting materials. The following procedures may exemplify certain embodiments of the invention, but other embodiments of the invention may use other methods, reagents and reagents using the same or similar methods or known to those skilled in the art. It should be understood that the same can be prepared by using starting materials. Where normal or preferred process conditions (eg, reaction temperature, number of times, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Please understand that you can. In some cases, the reaction was performed at room temperature and no actual temperature measurement was performed. It should be understood that room temperature can be taken to mean a temperature within the range typically associated with ambient temperature within the laboratory environment, and typically ranges from about 18 ° C to about 30 ° C. In other cases, the reaction was performed at room temperature and the temperature was actually measured and recorded. Optimum reaction conditions will usually vary depending on a variety of reaction parameters, such as the particular reactants used, solvents and amounts, but those skilled in the art will be able to use the appropriate optimization procedure using a given optimization procedure. Reaction conditions can be easily determined.

  Further, as will be apparent to those skilled in the art, conventional protecting groups may be necessary or desirable to prevent certain functional groups from undergoing undesired reactions. The selection of appropriate protecting groups for a particular functional group, and the selection of appropriate conditions and reagents for the protection and deprotection of such functional groups are well known in the art. If desired, protecting groups other than those exemplified in the procedures described herein can be used. For example, many protecting groups and their introduction and removal are described in T.W. W. Greene and G.M. M.M. Wuts, Protecting Groups in Organic Synthesis, 4th edition, Wiley, New York, 2006 and references cited therein.

Carboxy protecting groups are suitable to prevent undesired reactions at the carboxy group, such as, but not limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl (PMB), 9 -Fluorenylmethyl (Fm), trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM) and the like. Amino protecting groups are suitable for preventing undesired reactions at the amino group, such as, but not limited to, t-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz), 9- Fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) and the like can be mentioned. Hydroxyl protecting groups are suitable for preventing undesired reactions at hydroxyl groups, such as, but not limited to, C _1-6 alkyl, silyl groups (tri-C _1-6 alkylsilyl groups (eg trimethylsilyl (TMS ), Triethylsilyl (TES), and tert-butyldimethylsilyl (TBDMS)); esters (acyl groups) including C _1-6 alkanoyl groups such as formyl, acetyl, and pivaloyl, and aromatic Examples include acyl groups such as benzoyl; arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM).

Standard deprotection techniques and reagents are used to remove protecting groups, which may vary depending on which group is used. For example, sodium hydroxide or lithium hydroxide is commonly used when the carboxy protecting group is methyl, and when the carboxy protecting group is ethyl or t-butyl, an acid such as TFA or HCl is commonly used; When the carboxy protecting group is benzyl, H ₂ / Pd / C can be used. The BOC amino protecting group can be removed using acidic reagents such as TFA in DCM or HCl in 1,4-dioxane, while the Cbz amino protecting group can be removed in H ₂ (1 atm) and alcohol solvents. It can be removed by utilizing catalytic hydrogenation conditions such as 10% Pd / C (“H ₂ / Pd / C”). H ₂ / Pd / C is generally used when the hydroxyl protecting group is benzyl, while NaOH is generally used when the hydroxyl protecting group is an acyl group.

  Suitable bases for use in these schemes are, by way of example and not limitation, potassium carbonate, calcium carbonate, sodium carbonate, triethylamine, pyridine, 1,8-diazabicyclo- [5.4.0]. Undec-7-ene (DBU), N, N-diisopropylethylamine (DIPEA), 4-methylmorpholine, sodium hydroxide, potassium hydroxide, potassium t-butoxide, and metal hydrides.

Inert diluents or solvents suitable for use in these schemes include, by way of example and not limitation, tetrahydrofuran (THF), acetonitrile (MeCN), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), toluene, dichloromethane (DCM), chloroform (CHCl ₃ ), carbon tetrachloride (CCl ₄ ), 1,4-dioxane, methanol, ethanol, water, etc. .

  Suitable carboxylic acid / amine coupling reagents include benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), N , N, N ′, N′-tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU), 1,3-dicyclohexylcarbodiimide (DCC), N- (3-dimethyl Aminopropyl) -N′-ethylcarbodiimide (EDCI), carbonyldiimidazole (CDI), 1-hydroxybenzotriazole (HOBt) and the like. The coupling reaction is performed in an inert diluent in the presence of a base such as DIPEA and is performed under conventional amide bond forming conditions.

All reactions are usually performed at a temperature in the range of about -78 ° C to 100 ° C, such as room temperature. The reaction can be monitored until complete by the use of thin layer chromatography (TLC), high performance liquid chromatography (HPLC), and / or LCMS. The reaction may be completed in minutes or may take hours, usually 1-2 to 48 hours. Upon completion, the desired product can be obtained by further processing the resulting mixture or reaction product. For example, the resulting mixture or reaction product can be subjected to one or more of the following procedures: concentrated or partitioned (eg, between EtOAc and water, or 5% THF and 1M phosphoric acid in EtOAc) between); extraction (e.g., _EtOAc, CHCl 3, DCM, with chloroform); washing (for example, saturated aqueous NaCl, saturated aqueous _{NaHCO 3, Na 2 CO 3 (} 5%), the CHCl ₃ or 1M NaOH Dried) (eg, with MgSO ₄ , Na ₂ SO ₄ or in vacuo); filtered; crystallized (eg, from EtOAc and hexane); concentrated (eg, in vacuo); And / or purification (eg silica gel chromatography, flash chromatography, preparative HPLC, reverse phase HPLC Or crystallization).

  Compounds of formula I, as well as their salts, can be prepared as shown in Scheme I.

本プロセスは、化合物１と化合物２とのカップリングのステップを含み、Ｒ^１〜Ｒ^６、Ｘ、ａおよびｂは、式Ｉに対して定義された通りであり、Ｐ^１はＨまたは適切なアミノ保護基であり、このアミノ保護基の例として、ｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルが挙げられる。Ｐ^１がアミノ保護基の場合、本プロセスは、カップリングステップ前に、またはインサイチュで、式１の化合物を脱保護するステップをさらに含む。

The process includes a step of coupling compound 1 and compound 2, wherein R ^{1 to} R ⁶ , X, a and b are as defined for formula I and P ¹ is H or an appropriate Examples of amino protecting groups include t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl. When P ¹ is an amino protecting group, the process further includes deprotecting the compound of Formula 1 prior to the coupling step or in situ.

When R ¹ is a group such as —OCH ₃ or —OCH ₂ CH ₃ , a deprotection step may be performed after the coupling step to obtain a compound of formula I wherein R ¹ is a group such as —OH. it can. Thus, one method of preparing the compounds of the invention involves coupling compounds 1 and 2 with an optional deprotection step to form a compound of formula I or a pharmaceutically acceptable salt thereof. .

  The method for preparing compound 1 is described in the examples. Compound 2 is generally commercially available or can be prepared using procedures known in the art.

  Compounds of formula I, as well as their salts, can also be prepared as shown in Scheme II.

第１ステップにおいて、化合物１を化合物３とカップリングし、化合物３を化合物４とカップリングする。ここで、ＹおよびＺを、インサイチュで反応させて、Ｒ^３部分を形成する。例えば、Ｒ^３が−Ｃ（Ｏ）ＮＲ^２２Ｒ^２３の場合、Ｙは−ＣＯＯＨであり、ＺはＨＮＲ^２２Ｒ^２３である。あるいは、化合物３を最初に化合物４とカップリングし、次いで、得られた化合物を化合物１とカップリングする。スキームＩと同様に、Ｒ^１が−ＯＣＨ_３または−ＯＣＨ_２ＣＨ_３などの基の場合、カップリングステップの後に脱保護ステップを続けて、式Ｉの化合物（式中、Ｒ^１は−ＯＨなどの基である）を得ることができる。したがって、本発明の化合物を調製する１つの方法は、化合物１、２および３をカップリングすることを、式Ｉの化合物または薬学的に許容されるその塩を形成するための任意の脱保護ステップと共に含む。

In the first step, compound 1 is coupled with compound 3 and compound 3 is coupled with compound 4. Here, Y and Z are reacted in situ to form the R ³ moiety. For example, when R ³ is —C (O) NR ²² R ²³ , Y is —COOH and Z is HNR ²² R ²³ . Alternatively, compound 3 is first coupled with compound 4 and then the resulting compound is coupled with compound 1. As in Scheme I, when R ¹ is a group such as —OCH ₃ or —OCH ₂ CH ₃ , a coupling step is followed by a deprotection step to form a compound of formula I wherein R ¹ is —OH, etc. Which is a group of Thus, one method of preparing the compounds of the invention involves coupling compounds 1, 2 and 3 with an optional deprotection step to form a compound of formula I or a pharmaceutically acceptable salt thereof. Include with.

  Compounds 3 and 4 are generally commercially available or can be prepared using procedures known in the art.

  Compounds of formula I, as well as their salts, can also be prepared as shown in Scheme III: {based on Example 9}.

この場合もスキームＩおよびＩＩと同様に、これは、式Ｉの化合物（式中、Ｒ^１は−ＮＲ^８Ｒ^９である）を生成するための、式Ｉの化合物（式中、Ｒ^１は−ＯＨである）と化合物５の間の標準的なカップリング反応である。

As with this case Schemes I and II, which is a compound of formula I (wherein, ^{R 1} is ^-NR 8 ^{R 9)} for producing a compound of formula I (wherein, ^{R 1} is Standard coupling reaction between compound 5 and -OH.

  Certain intermediates described herein are considered novel and thus such compounds are described, for example, by the formula 1

の化合物またはその塩を含む、本発明のさらなる態様として提供される（式中、Ｐ^１は、Ｈであるか、またはｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基であり、Ｒ^１、Ｒ^２、Ｒ^５、Ｒ^６、ａおよびｂは、式Ｉに対して定義された通りである）。本発明の別の中間体は、式６

Or a salt thereof is provided as a further aspect of the invention wherein P ¹ is H or t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, An amino protecting group selected from formyl, trimethylsilyl, and t-butyldimethylsilyl, R ¹ , R ² , R ⁵ , R ⁶ , a and b are as defined for Formula I). Another intermediate of the invention is represented by formula 6

を有するものまたはその塩である（式中、Ｒ^１Ｐは、−Ｏ−Ｐ^３、−ＮＨＰ^２、および−ＮＨ（Ｏ−Ｐ^４）から選択され、Ｐ^２は、ｔ−ブトキシカルボニル、トリチル、ベンジルオキシカルボニル、９−フルオレニルメトキシカルボニル、ホルミル、トリメチルシリル、およびｔ−ブチルジメチルシリルから選択されるアミノ保護基であり、Ｐ^３は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ^４は、−Ｃ_１〜６アルキル、トリＣ_１〜６アルキルシリル、−Ｃ_１〜６アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基であり、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、ａ、ｂ、およびＸは、式Ｉに対して定義された通りである）。本発明の別の中間体は、式７

Wherein R ^1P is selected from —O—P ³ , —NHP ² , and —NH (O—P ⁴ ), wherein P ² is t-butoxycarbonyl, trityl, benzyloxycarbonyl, a 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyl amino-protecting group selected from dimethyl silyl, P ³ is methyl, ethyl, t- butyl, benzyl, p- methoxybenzyl , 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl, P ⁴ is —C _1-6 alkyl, tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and di A hydroxyl protecting group selected from phenylmethyl, wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , a, b, and X are as defined for formula I). Another intermediate of the invention is represented by formula 7

を有するものまたはその塩である（式中、Ｒ^３Ｐは、−Ｃ_０〜５アルキレン−Ｏ−Ｐ^４、−Ｃ_０〜１アルキレン−ＣＯＯ−Ｐ^３、および−Ｏ−Ｐ^４で置換されているフェニルから選択され、Ｐ^３は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ^４は、−Ｃ_１〜６アルキル、トリＣ_１〜６アルキルシリル、−Ｃ_１〜６アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基であり、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、ａ、ｂ、およびＸは、式Ｉに対して定義された通りである）。本発明のさらなる別の中間体は、式８

Wherein R ^3P is substituted with —C _0-5 alkylene-O—P ⁴ , —C _0-1 alkylene-COO—P ³ , and —O—P ^4. A carboxy protecting group selected from phenyl, wherein P ³ is selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl And P ⁴ is selected from —C _1-6 alkyl, tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl. a hydroxyl protecting ^{group, R 1, R 2, R} 4, R 5, R 6, a, b, and X, through defined for formula I In is). Yet another intermediate of the invention is a compound of formula 8

を有するものまたはその塩である（式中、Ｒ^４Ｐは、−Ｏ−Ｐ^４；−Ｃ_１〜２アルキレン−ＣＯＯ−Ｐ^３；および−ＣＯＯ−Ｐ^３で置換されているフェニルまたはベンジルから選択され、Ｐ^３は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ^４は、−Ｃ_１〜６アルキル、トリＣ_１〜６アルキルシリル、−Ｃ_１〜６アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基であり、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｒ^６、ａ、ｂ、およびＸは、式Ｉに対して定義された通りである）。本発明のさらに別の中間体は、式９

Wherein R ^4P is selected from —O—P ⁴ ; —C _1-2 alkylene-COO—P ³ ; and phenyl or benzyl substituted with —COO—P ³ P ³ is a carboxy protecting group selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl; ⁴ is a hydroxyl protection selected from —C _1-6 alkyl, tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl. The groups R ¹ , R ² , R ³ , R ⁵ , R ⁶ , a, b, and X are as defined for formula I is there). Yet another intermediate of the invention is a compound of formula 9

を有するものまたはその塩である（式中、Ｒ^３Ｐは、−Ｃ_０〜５アルキレン−Ｏ−Ｐ^４、−Ｃ_０〜１アルキレン−ＣＯＯ−Ｐ^３、および−Ｏ−Ｐ^４で置換されているフェニルから選択され、Ｒ^４Ｐは、−Ｏ−Ｐ^４；−Ｃ_１〜２アルキレン−ＣＯＯ−Ｐ^３、および−ＣＯＯ−Ｐ^３で置換されているフェニルまたはベンジルから選択され、Ｐ^３は、メチル、エチル、ｔ−ブチル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、トリメチルシリル、ｔ−ブチルジメチルシリル、およびジフェニルメチルから選択されるカルボキシ保護基であり、Ｐ^４は、−Ｃ_１〜６アルキル、トリＣ_１〜６アルキルシリル、−Ｃ_１〜６アルカノイル、ベンゾイル、ベンジル、ｐ−メトキシベンジル、９−フルオレニルメチル、およびジフェニルメチルから選択されるヒドロキシル保護基であり、Ｒ^１、Ｒ^２、Ｒ^５、Ｒ^６、ａ、ｂ、およびＸは、式Ｉに対して定義された通りである）。したがって、本発明の化合物を調製する別の方法は、式１、６、７、８、９の化合物またはその塩を脱保護するステップを含む。

Wherein R ^3P is substituted with —C _0-5 alkylene-O—P ⁴ , —C _0-1 alkylene-COO—P ³ , and —O—P ^4. R ^4P is selected from phenyl or benzyl substituted with —O—P ⁴ ; —C _1-2 alkylene-COO—P ³ , and —COO—P ³ , wherein P ³ is A carboxy protecting group selected from methyl, ethyl, t-butyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t-butyldimethylsilyl, and diphenylmethyl, P ⁴ is —C _{1 6} alkyl, tri _{C 1 to 6} alkyl _{silyl, -C 1 to 6} alkanoyl, benzoyl, benzyl, p- methoxybenzyl, 9-fluorenylmethyl, and di A hydroxyl protecting group selected from ^{Enirumechiru, R 1, R 2, R} 5, R 6, a, b, and X are as defined for formula I). Accordingly, another method of preparing the compounds of the present invention involves deprotecting a compound of Formula 1, 6, 7, 8, 9, or a salt thereof.

  Additional details regarding specific reaction conditions and other procedures for preparing representative compounds of the invention or intermediates thereof are described in the Examples set forth below.

Utility The compounds of the present invention possess neprilysin (NEP) inhibitory activity, i.e., the compounds can inhibit enzyme catalytic activity. In another embodiment, the compound does not exhibit significant inhibitory activity of angiotensin converting enzyme. One measure of the ability of a compound to inhibit NEP activity is the inhibition constant (pK _i ). This pK _i value is the negative logarithm to the base 10 of the dissociation constant (K _i ), which is usually reported in moles. Particularly interesting compounds of the present invention, those having a 6.0 or more pK _i at NEP, in particular those with more than 7.0 pK _i, even more specifically one having a 8.0 or more pK _i is there. In one embodiment, the interesting compound has a pK _i in the range of 6.0-6.9, and in another embodiment, the interesting compound has a pK _i in the range of 7.0-7.9. In yet another embodiment, the interesting compound has a pK _i in the range of 8.0 to 8.9, and in yet another embodiment, the interesting compound has a pK _i in the range of 9.0 or higher. . Such values can be determined by techniques well known in the art, as well as in the assays described herein.

Another measure of the ability of a compound to inhibit NEP activity is the apparent inhibition constant (IC ₅₀ ), which is the molar concentration of the compound that results in half-maximal inhibition of substrate conversion by the NEP enzyme. The pIC ₅₀ value is the negative logarithm for the base 10 of the IC ₅₀ . Particularly interesting compounds of the invention include those that exhibit a pIC _{50 of} about 5.0 or greater relative to NEP. Interesting compounds also comprise those with _{pIC 50} or _{pIC 50} of ≧ about 7.0 against NEP of ≧ about 6.0 against NEP. In another embodiment, the compound of interest has a pIC ₅₀ in the range of about 7.0-11.0 relative to NEP, and in another embodiment, in the range of about 8.0-11.0, For example, it has a pIC ₅₀ in the range of about 8.0 to 10.0.

  It should be noted that in some cases, compounds of the present invention may possess weak NEP inhibitory activity. In such cases, those skilled in the art recognize that these compounds still have utility as research tools.

  Exemplary assays for determining the properties of the compounds of the invention, such as NEP inhibitory activity, are described in the Examples and are illustrative and non-limiting assays that measure NEP inhibition (assays). 1). Useful second assays include ACE inhibition (also described in Assay 1) and aminopeptidase P (APP) inhibition (Sulpizio et al. (2005) JPET, 315: 3063-1313. Assay). A pharmacodynamic assay for assessing the in vivo inhibitory potency for ACE and NEP in anesthetized rats has been described in Assay 2 (Seymour et al. (1985) Hypertension, 7 (Appendix I): I -35-I-42 and Wigle et al. (1992) Can. J. Physiol. Pharmacol. 70: 1525-1528), ACE inhibition is the inhibition of the angiotensin I pressor response (percent). NEP inhibition is measured as increased urinary cyclic guanosine 3 ′, 5′-monophosphate (cGMP) output.

  There are many in vivo assays that can be used to confirm the further utility of the compounds of the present invention. The conscious spontaneously hypertensive rat (SHR) model is a renin-dependent hypertension model and is described in Assay 3. See also Intengan et al. (1999) Circulation, 100 (22): 2267-2275 and Badyal et al. (2003) Indian Journal of Pharmacology, 35: 349-362. The conscious desoxycorticosterone acetate (DOCA salt) rat model is a dose-dependent hypertension model useful for measuring NEP activity and is described in Assay 4. Trapani et al. (1989) J. MoI. Cardiovasc. Pharmacol. 14: 419-424, Intengan et al. (1999) Hypertension 34 (4): 907-913 and Badyal et al. (2003) (see above). The DOCA salt model is particularly useful for assessing the ability of a test compound to reduce blood pressure as well as measuring the ability of a test compound to prevent or delay an increase in blood pressure. The Dahl salt sensitive (DSS) hypertensive rat model is a model of hypertension sensitive to salt (NaCl) and is described in Assay 5. See also Rapp, (1982) Hypertension, 4: 753-763. Rat monocrotaline models of pulmonary arterial hypertension are described in, for example, Kato et al. (2008) J. MoI. Cardiovasc. Pharmacol. 51 (1): 18-23, this model is a reliable predictor of clinical efficacy for the treatment of pulmonary arterial hypertension. Examples of animal models of heart failure include the DSS rat model for heart failure and the great arteriovenous fistula model (AV shunt), which are described in, for example, Norling et al. (1996) J. MoI. Amer. Soc. Nephrol. 7: 1038-1044. Other animal models can be used to measure the analgesic properties of the compounds of the present invention, such as hot plate, tail-flick and formalin tests, as well as the spinal nerve ligation (SNL) model of neuropathic pain. See, for example, Malmberg et al. (1999) Current Protocols in Neuroscience 8.9.1 to 8.9.15.

  The compounds of the invention are expected to inhibit the NEP enzyme in any of the assays listed above, or in assays of similar nature. Thus, the above-described assays are useful in determining the therapeutic utility of the compounds of the present invention, such as their antihypertensive or antidiarrheal agents. Other properties and utilities of the compounds of the present invention can be demonstrated using other in vitro and in vivo assays well known to those skilled in the art. The compounds of formula I may be active drugs as well as prodrugs. Thus, when considering the activity of the compounds of the present invention, any such prodrug may not exhibit the expected activity in the assay but is expected to exhibit the desired activity when metabolized. Please understand that.

  The compounds of the present invention are expected to be useful for the treatment and / or prevention of medical conditions in response to NEP inhibition. Thus, a patient suffering from a disease or disorder treated by inhibiting the NEP enzyme or by increasing the level of its peptide substrate, is treated by administering a therapeutically effective amount of a compound of the invention. It is expected that it can be done. For example, by inhibiting NEP, compounds can be produced by endogenous peptides metabolized by NEP, such as natriuretic peptides, bombesin, bradykinin, calcitonin, endothelin, enkephalin, neurotensin, substance P and vasoactive intestinal peptides. It is expected to enhance biological effects. Thus, these compounds are expected to have other physiological effects on, for example, the kidney, central nervous system, reproductive and digestive systems.

In one embodiment of the invention, a patient suffering from a disease or disorder treated by inhibiting the NEP enzyme is an active form of a compound of the invention, ie a compound of formula I (wherein R ¹ Is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, R ⁸ is H or —OH, R ⁹ is H, R ^{2 to} R ⁶ , a, b, and X Is as defined for formula I).

In another embodiment, the patient is metabolized in vitro to form a compound of formula I wherein R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, and R ⁸ Treated by administering a compound that forms H) or -OH, R ⁹ is H, and R ^{2 to} R ⁶ , a, b, and X are as defined for formula I) Is done. In an exemplary embodiment, the patient administers a compound that is metabolized in vitro to form a compound of formula III, wherein R ¹ is —OR ⁷ and R ⁷ is H. Treated by.

In another embodiment, the patient has a compound of the invention that is in its prodrug form at the R ¹ group, ie a compound of formula I
R ¹ is —OR ⁷ and R ⁷ is —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{C3-7cycloalkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene _{^{-OC (O) R 10, -C}} 1~6 alkylene ^-NR 12 ^R 13, -C _{1 -6} alkylene-C (O) R ³¹ , -C _0-6 alkylenemorpholinyl, -C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

から選択されるか、または
Ｒ^１は、−ＮＲ^８Ｒ^９であり、Ｒ^８は、−ＯＣ（Ｏ）Ｒ^１４、−ＣＨ_２ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^９はＨであるか、または
Ｒ^１は−ＮＲ^８Ｒ^９であり、Ｒ^８は、−ＯＣ（Ｏ）Ｒ^１４、−ＣＨ_２ＣＯＯＨ、−Ｏ−ベンジル、ピリジル、および−ＯＣ（Ｓ）ＮＲ^１５Ｒ^１６から選択され、Ｒ^９は、−Ｃ_１〜６アルキルもしくは−Ｃ（Ｏ）Ｒ^１７であり、
Ｒ^１は、−ＮＲ^８Ｒ^９であり、Ｒ^８は、Ｈもしくは−ＯＨから選択され、Ｒ^９は、−Ｃ_１〜６アルキルおよび−Ｃ（Ｏ）Ｒ^１７から選択され、
Ｒ^１は−ＯＲ^７であり、Ｒ^２はＲ^７と一緒になって−ＣＲ^１８Ｒ^１９−を形成するか、または
Ｒ^１は−ＮＲ^８Ｒ^９であり、Ｒ^２はＲ^８と一緒になって、−Ｃ（Ｏ）−を形成し、
Ｒ^１０、Ｒ^１２〜Ｒ^１７、Ｒ^３１、Ｒ^３２、Ｒ^３〜Ｒ^６、ａ、ｂ、およびＸは、式Ｉに対して定義された通りである）を投与することによって処置される。典型的な実施形態では、患者は、Ｒ^１基においてそのプロドラッグ形態であり、式ＩＩＩを有する本発明の化合物を投与することによって処置される。

Or R ¹ is —NR ⁸ R ⁹ , where R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR. ¹⁵ R ^{16 is} selected and R ⁹ is H or R ¹ is —NR ⁸ R ⁹ and R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl. And —OC (S) NR ¹⁵ R ¹⁶ , wherein R ⁹ is —C _1-6 alkyl or —C (O) R ¹⁷ ;
R ¹ is —NR ⁸ R ⁹ , R ⁸ is selected from H or —OH, R ⁹ is selected from —C _1-6 alkyl and —C (O) R ¹⁷ ;
R ¹ is —OR ⁷ and R ² together with R ⁷ forms —CR ¹⁸ R ¹⁹ — or R ¹ is —NR ⁸ R ⁹ and R ² together with R ⁸ To form -C (O)-
R ¹⁰ , R ¹² -R ¹⁷ , R ³¹ , R ³² , R ³ -R ⁶ , a, b, and X are as defined for Formula I). In an exemplary embodiment, the patient is treated by administering a compound of the invention that is in its prodrug form at the R ¹ group and has Formula III.

Cardiovascular Diseases By enhancing the action of vasoactive peptides such as natriuretic peptides and bradykinin, the compounds of the present invention find utility in treating and / or preventing medical conditions such as cardiovascular diseases. Is expected. See, for example, Roques et al. (1993) Pharmacol. Rev. 45: 87-146 and Dempsey et al. (2009) Amer. J. et al. of Pathology, 174 (3): 782-796. Particularly interesting cardiovascular diseases include hypertension and heart failure. Hypertension, by way of example, includes, but is not limited to: primary hypertension (also referred to as essential or idiopathic hypertension); secondary hypertension; hypertension with associated renal disease; Severe hypertension with or without kidney disease; pulmonary hypertension (including pulmonary arterial hypertension); and treatment-resistant hypertension. Examples of heart failure include, but are not limited to: congestive heart failure; acute heart failure; chronic heart failure, such as those with reduced left ventricular ejection fraction (also called systolic heart failure) or left ventricular drive Preserved rate (also called diastolic heart failure); and acute and chronic decompensated heart failure (with and without associated renal disease). Accordingly, one embodiment of the invention relates to a method of treating hypertension, particularly primary or pulmonary arterial hypertension, comprising administering to a patient a therapeutically effective amount of a compound of the invention.

For the treatment of primary hypertension, a therapeutically effective amount is usually an amount sufficient to reduce a patient's blood pressure. This includes both mild to moderate hypertension and severe hypertension. When used to treat hypertension, the compounds may include other therapeutic agents such as aldosterone antagonists, aldosterone synthase inhibitors, angiotensin converting enzyme inhibitors and dual acting angiotensin converting enzyme / neprilysin inhibitor, angiotensin converting enzyme 2 ( ACE2) activators and stimulators, angiotensin-II vaccines, antidiabetics, antilipids, antithrombotics, AT ₁ receptor antagonists and dual acting AT ₁ receptor antagonists / neprilysin inhibitors, β ₁ -adrenergic receptors body antagonists, dual-acting β- adrenergic receptor antagonist / alpha ₁ - receptor antagonists, calcium channel blockers, diuretics, endothelin receptor antagonists, endothelin converting enzyme inhibitors, Nepurira Syn inhibitors, natriuretic peptides and analogs thereof, natriuretic peptide clearance receptor antagonists, nitric oxide donors, nonsteroidal anti-inflammatory agents, phosphodiesterase inhibitors (specifically PDE-V inhibitors), prostagland It can be administered in combination with gin receptor agonists, renin inhibitors, soluble guanylate cyclase stimulators and activators and combinations thereof. In one particular embodiment of the invention, the compounds of the invention are used to treat primary hypertension in combination with an AT ₁ receptor antagonist, calcium channel blocker, diuretic, or combinations thereof. . In another specific embodiment of the invention, the compounds of the invention are used in combination with an AT ₁ receptor antagonist to treat hypertension associated with concomitant renal disease. When used to treat refractory hypertension, the compounds can be administered in combination with other therapeutic agents such as aldosterone synthase inhibitors.

For the treatment of pulmonary arterial hypertension, the therapeutically effective amount is usually an amount sufficient to reduce pulmonary vascular resistance. Another goal of therapy is to improve the patient's ability to exercise. For example, in a clinical situation, a therapeutically effective amount can be an amount that improves the patient's ability to walk comfortably for a period of 6 minutes (over a distance of about 20-40 meters). When used to treat pulmonary arterial hypertension, the compounds may be used as other therapeutic agents such as α-adrenergic receptor antagonists, β ₁ -adrenergic receptor antagonists, β ₂ -adrenergic receptor agonists, angiotensin converting enzyme inhibitors, It can be administered in combination with clotting agents, calcium channel blockers, diuretics, endothelin receptor antagonists, PDE-V inhibitors, prostaglandin analogs, selective serotonin reuptake inhibitors, and combinations thereof. In one particular embodiment of the invention, the compounds of the invention are used to treat pulmonary arterial hypertension in combination with a PDE-V inhibitor or a selective serotonin reuptake inhibitor.

Another embodiment of the present invention comprises heart failure, particularly congestive heart failure (including both systolic and diastolic congestive heart failure) comprising administering to a patient a therapeutically effective amount of a compound of the present invention. It relates to a method for treating. Usually, a therapeutically effective amount is an amount sufficient to lower blood pressure and / or improve renal function. In clinical situations, a therapeutically effective amount can be an amount sufficient to improve cardiac hemodynamics, such as a decrease in wedge pressure, right atrial pressure, filling pressure, and vascular resistance. In one embodiment, the compound is administered as an intravenous dosage form. When used to treat heart failure, the compounds may be other therapeutic agents such as adenosine receptor antagonists, advanced glycation end product breakers, aldosterone antagonists, AT ₁ receptor antagonists, β ₁ -adrenergic receptor antagonists, dual action Β-adrenergic receptor antagonist / α ₁ -receptor antagonist, chymase inhibitor, digoxin, diuretic, endothelin converting enzyme (ECE) inhibitor, endothelin receptor antagonist, natriuretic peptide and analogs thereof, natriuretic peptide Clearance receptor antagonists, nitric oxide donors, prostaglandin analogs, PDE-V inhibitors, soluble guanylate cyclase activators and stimulators, and vasopressin receptor antagonists It may be administered in combination with a like. In one particular embodiment of the invention, the compounds of the invention are used in combination with aldosterone antagonists, β ₁ -adrenergic receptor antagonists, AT ₁ receptor antagonists, or diuretics to treat congestive heart failure. Is done.

Diarrhea As a NEP inhibitor, the compounds of the present invention are expected to inhibit the degradation of endogenous enkephalins, and therefore such compounds are useful for the treatment of diarrhea, including infectious and secreted / watery diarrhea. Also usefulness can be found. See, for example, Baumer et al. (1992) Gut, 33: 753-758; Farthing (2006) Digestive Diseases, 24: 47-58; and Marcais-Collado (1987) Eur. J. et al. Pharmacol. 144 (2): 125-132. When used to treat diarrhea, the compounds of the invention can be used in combination with one or more additional antidiarrheal agents.

Renal disease By enhancing the action of vasoactive peptides such as natriuretic peptides and bradykinin, the compounds of the present invention improve renal function (Chen et al. (1999) Circulation, 100: 2443-1448; Lipkin et al. (1997) Kidney Int. 52: 792-801; and Dussaule et al. (1993) Clin. Sci. 84: 31-39), treatment of renal disease and / or It is expected to find utility in prevention. Particularly interesting renal diseases include diabetic nephropathy, chronic kidney disease, proteinuria, and especially acute kidney injury or acute renal failure (Sharkovska et al. (2011) Clin. Lab. 57: 507-515 and Newaz et al. (2010) Renal Failure, 32: 384-390). When used to treat renal disease, the compounds can be administered in combination with other therapeutic agents, such as angiotensin converting enzyme inhibitors, AT ₁ receptor antagonists, diuretics and the like.

Prophylactic Therapy By enhancing the action of natriuretic peptides, the compounds of the invention can also be used in prophylactic therapy due to the antihypertrophic and antifibrotic effects of natriuretic peptides (Potter et al. (2009) Handbook of Experimental Pharmacology, 191: pp. 341-366), for example, preventing the progression of cardiac dysfunction after myocardial infarction, preventing arterial restenosis after angioplasty, and increasing vascular wall thickening after vascular surgery It is also expected to be useful in preventing, preventing atherosclerosis, and preventing diabetic vasculopathy.

Glaucoma By enhancing the action of natriuretic peptides, the compounds of the present invention are expected to be useful for treating glaucoma. See, for example, Diestelhorst et al. (1989) International Ophthalmology, 12: 99-101. When used to treat glaucoma, the compounds of the invention can be used in combination with one or more additional anti-glaucoma agents.

Pain Relief As NEP inhibitors, the compounds of the present invention are expected to inhibit the degradation of endogenous enkephalins, and therefore such compounds can also find utility as analgesics. See, for example, Roques et al. (1980) Nature, 288: 286-288 and Thanawala et al. (2008) Current Drug Targets, 9: 887-894. When used to treat pain, the compounds of the present invention may contain one or more additional antinociceptive drugs, such as aminopeptidase N or dipeptidyl peptidase III inhibitors, non-steroidal anti-inflammatory agents, monoamine recombination. It can be used in combination with uptake inhibitors, muscle relaxants, NMDA receptor antagonists, opioid receptor agonists, 5-HT _1D serotonin receptor agonists, tricyclic antidepressants and the like.

Other Useful Due to these NEP inhibitory properties, the compounds of the present invention are also expected to be useful as antitussives, as well as portal hypertension associated with cirrhosis (Sansoe et al. (2005) J. MoI. Hepatol. 43: see 791-798), cancer (Vesery, (2005) J. Investigative Med. 53: 360-365), depression (Noble et al., (2007). Year) Exp.Opin.Ther.Targets, 11: 145-159), menstrual disorders, preterm labor, preeclampsia, endometriosis, reproductive disorders (eg, male and female infertility, multiple Cystic ovary syndrome, implantation failure), and male and female sexual dysfunction, including male erectile dysfunction and female sexual arousal disorder Utility in treatment has been found. More specifically, the compounds of the present invention are expected to be useful for treating female sexual dysfunction (Pryde et al. (2006) J. Med. Chem. 49: 4409-4424. (See page), this sexual dysfunction is often defined as the difficulty or inability of female patients to find satisfaction in sexual expression. Sexual dysfunction covers a wide variety of female sexual illnesses, including but not limited to hyposexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder. When used to treat such diseases, particularly female sexual dysfunction, the compounds of the invention may be used in combination with one or more of the following second agents: PDE-V inhibition Agents, dopamine agonists, estrogen receptor agonists and / or antagonists, androgens, and estrogens. Due to these NEP inhibitory properties, the compounds of the present invention are also expected to have anti-inflammatory properties, and thus are expected to have utility, particularly when used in combination with statins.

  Recent studies suggest that NEP plays a role in regulating neuronal function in hypoinsulinemia and diet-induced obesity. Coppey et al. (2011) Neuropharmacology 60: 259-266. Thus, due to these NEP inhibitory properties, the compounds of the invention are also expected to be useful in providing protection against neurological dysfunction caused by diabetes or diet-induced obesity.

  The amount administered per day or the total amount administered per day of a compound of the invention may be predetermined, or the nature and severity of the patient's condition, the condition being treated, the age of the patient , Weight, and general health, patient tolerance to active agents, route of administration, pharmacological considerations such as activity, potency, pharmacokinetics and toxicology profiles of the administered compound and any second agent, etc. It may be determined on an individual patient basis by taking into account many factors that have been included. Treatment of a patient suffering from a disease or medical condition (such as hypertension) can be initiated using a predetermined dose or a dose determined by the treating physician to prevent symptoms of the disease or medical condition Will continue for a period of time necessary to improve, control or reduce. Patients undergoing such treatment usually determine the effectiveness of the therapy by daily monitoring. For example, in the treatment of hypertension, the effectiveness of the treatment can be determined by using blood pressure measurements. Similar indicators for the other diseases and conditions described herein are well known and readily available to the treating physician. Continuous monitoring by the physician ensures that the optimal amount of the compound of the invention is administered at any given time and facilitates the determination of the treatment period. This is particularly important when a second agent is also administered, as adjustments to these selections, doses, and duration of therapy may be required. Thus, the treatment regimen and dosing regimen is such that the lowest amount of active agent that exhibits the desired efficacy is administered, and that the administration continues for as long as necessary to successfully treat the disease or medical condition. Can be adjusted across the course.

Research Tools Since the compounds of the present invention possess NEP enzyme inhibitory activity, such compounds may also be used to investigate or study biological systems or samples that have NEP enzymes, such as the role of NEP enzymes or their peptide substrates. It is also useful as a research tool to study the disease that it plays. Any suitable biological system or sample having a NEP enzyme can be utilized in such studies that can be performed either in vitro or in vivo. Representative biological systems or samples suitable for such studies include, but are not limited to, cells, cell extracts, plasma membranes, tissue samples, isolated organs, mammals (eg, mice, Rats, guinea pigs, rabbits, dogs, pigs, humans, etc.), and mammals are of particular interest. In one particular embodiment of the invention, NEP enzyme activity in a mammal is inhibited by administering a NEP inhibitory amount of a compound of the invention. The compounds of the present invention can also be used as research tools by conducting biological assays using such compounds.

  When used as a research tool, a biological system or sample containing NEP enzyme is usually contacted with a NEP enzyme inhibitory amount of a compound of the invention. After exposing a biological system or sample to a compound, using conventional procedures and equipment, for example, by measuring receptor binding in a binding assay, or by measuring a ligand-mediated change in a functional assay To determine the action of inhibiting the NEP enzyme. Exposure involves contacting a cell or tissue with the compound, eg, i. p. , P. o, i. v. , S. c. Or administration of the compound to a mammal, such as by inhalation. This determining step can include measuring a response (quantitative analysis) or can include observing (qualitative analysis). Measuring the response includes determining the effect of the compound on the biological system or sample using, for example, conventional procedures and equipment, such as enzyme activity assays, and mediating enzyme substrates or products in functional assays. Including measuring changes to be made. The results of the assay can be used to determine the level of activity as well as the amount of compound required to achieve the desired result, ie, the amount of NEP enzyme inhibition. Typically, this determination step will include determining an action that inhibits the NEP enzyme.

Furthermore, the compounds of the present invention can be used as research tools to evaluate other chemicals and are therefore useful, for example, in screening assays to discover new compounds with NEP inhibitory activity. Thus, use of a compound of the present invention as a standard in an assay allows comparison of results obtained using a test compound with results obtained using a compound of the present invention, which are approximately equal or If so, identify test compounds with better activity. For example, by comparing pK _i data for a test compound or group of test compounds with pK _i data for a compound of the present invention, a test compound having the desired property, eg, a compound of the present invention is approximately equal, Or, if any, identify a test compound with a superior pK _i value. This aspect of the invention includes as separate embodiments both the generation of comparative data (using an appropriate assay) and the analysis of test data to identify interesting test compounds. Accordingly, a test compound is obtained in a biological assay by: (a) conducting a biological assay using the test compound to obtain a first assay value; and (b) using the compound of the present invention Performing a secondary assay to obtain a second assay value; and (c) comparing the first assay value obtained in step (a) with the second assay value obtained in step (b); And step (a) can be evaluated by a method performed before, after or simultaneously with step (b). Typical biological assays include NEP enzyme inhibition assays.

Pharmaceutical Compositions and Formulations Compounds of the present invention are usually administered to a patient in the form of a pharmaceutical composition or formulation. Such pharmaceutical compositions may be any, including but not limited to oral, rectal, vaginal, nasal, inhalation, topical (including transdermal), ocular, and parenteral modes of administration. It can be administered to a patient by an acceptable route of administration. In addition, the compounds of the invention may be administered, for example, orally, multiple times per day (eg, daily, 2, 3, or 4 times), a single daily dose, or a weekly dose A single dose can be administered. Any form of the compound of the invention suitable for a particular mode of administration (ie, free base, free acid, pharmaceutically acceptable salt, solvate, etc.) is discussed herein. It should be understood that it can be used in pharmaceutical compositions.

  Thus, in one embodiment, the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the invention. The composition may contain other therapeutic agents and / or combination agents, if desired. When discussing the compositions, the “compounds of the invention” may also be referred to herein as “active agents” and can be distinguished from other ingredients of the formulation, such as a carrier. Thus, it is to be understood that the term “active agent” includes compounds of formula I and pharmaceutically acceptable salts, solvates and prodrugs of that compound.

  The pharmaceutical compositions of the invention usually contain a therapeutically effective amount of a compound of the invention. However, those skilled in the art will appreciate that pharmaceutical compositions, such as bulk compositions, may contain more than a therapeutically effective amount, or less than a therapeutically effective amount, ie, by multiple administrations. It will be appreciated that individual unit doses that are planned to achieve a therapeutically effective amount may be included. Typically, the composition will contain about 0.01 to 95% by weight of active agent (including about 0.01 to 30% by weight, including about 0.01 to 10% by weight) in actual amounts. Depends on the formulation itself, the route of administration, the frequency of dosing and the like. In one embodiment, a composition suitable for an oral dosage form may contain, for example, about 5-70 wt%, or about 10-60 wt% active agent.

  Any conventional carrier or excipient can be used in the pharmaceutical compositions of the invention. The choice of a particular carrier or excipient, or combination of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical or disease state become. In this regard, the preparation of a suitable composition for a particular type of administration is well within the scope of those skilled in the pharmaceutical arts. In addition, carriers or excipients used in such compositions are commercially available. By way of further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & White, Baltimore, Maryland (2000); C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition, Lippincott Williams & White, Baltimore, Maryland (1999).

  Representative examples of substances that can function as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose, For example, microcrystalline cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil , Safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol Esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer solution; Alcohol; phosphate buffer; compressed propellant gases, such as chlorofluorocarbons and hydrofluorocarbons; and other non-toxic compatible materials utilized in pharmaceutical compositions.

  A pharmaceutical composition is typically prepared by thoroughly or intimately mixing or blending an active agent with a pharmaceutically acceptable carrier and one or more optional ingredients. The resulting uniformly blended mixture can then be shaped or filled into tablets, capsules, pills, canisters, cartridges, dispensers, etc. using conventional procedures and equipment.

  In one embodiment, the pharmaceutical composition is suitable for oral administration. Compositions suitable for oral administration include capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; solutions or suspensions in aqueous or non-aqueous liquids; oil-in-water or Water-in-oil liquid emulsions; may be in the form of elixirs or syrups, each containing a predetermined amount of active agent.

  When intended for oral administration in a solid dosage form (capsule, tablet, pill, etc.), the composition typically comprises an active agent and one or more pharmaceutically acceptable carriers, such as sodium citrate or Dicalcium phosphate etc. will be included. Solid dosage forms may also include: fillers or bulking agents such as starch, microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethyl cellulose, alginate, Moisturizers such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and / or sodium carbonate; Absorption enhancers such as quaternary ammonium compounds; Wetting agents such as cetyl alcohol and / or glycerol monostearate; Absorbents such as kaolin and / or And night clay; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and / or mixtures thereof and the like; coloring agents; and buffering agents.

  Release agents, wetting agents, coating agents, sweetening, flavoring and fragrances, preservatives and antioxidants may also be present in the pharmaceutical composition. Typical coatings for tablets, capsules, pills, etc., those used for enteric coatings, such as cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylic acid ester copolymer, trimellitate Acid cellulose acetate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate and the like can be mentioned. Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfate, sodium sulfite, etc .; oil-soluble antioxidants For example, ascorbyl palmitate, butylated hydroxyanisole, butylhydroxytoluene, lecithin, propyl gallate, alpha tocopherol and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid and the like.

  The composition may also be formulated to provide sustained or controlled release of the active agent using, for example, various proportions of hydroxypropyl methylcellulose or other polymer matrix, liposomes and / or microspheres, etc. Can be done. Furthermore, the pharmaceutical compositions of the present invention may contain opacifiers, and the pharmaceutical compositions of the present invention require the active agent only in or preferentially in certain parts of the digestive tract. May be formulated to be released in a delayed format. Examples of embedding compositions that can be used include polymeric substances and waxes. The active agent can also be in microencapsulated form, optionally with one or more of the above excipients.

  Liquid dosage forms suitable for oral administration include, by way of illustration, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms are usually active and inert diluents such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (eg cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof. The suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. .

  When intended for oral administration, the pharmaceutical compositions of the invention may be packaged in a unit dosage form. The term “unit dosage form” refers to a physically discrete unit suitable for patient administration, ie, each unit alone or in combination with one or more additional units as desired. A predetermined amount of active agent calculated to produce a therapeutic effect of For example, such unit dosage forms may be capsules, tablets, pills, and the like.

  In another embodiment, the compositions of the invention are suitable for administration by inhalation and are usually in the form of an aerosol or powder. Such compositions are generally administered using well-known delivery devices such as nebulizers, dry powders or metered dose inhalers. The nebulizer device generates a high velocity air flow that causes the composition to be sprayed as a mist that is carried into the patient's respiratory tract. A typical nebulizer formulation includes an active agent that dissolves in a carrier to form a solution, or an active agent that is micronized and mixed with the carrier to form a suspension of micronized particles of a size suitable for respiration. . Dry powder inhalers administer the active agent as a free-flowing powder that disperses in the patient's air stream during inspiration. A typical dry powder formulation includes an active agent dry blended with excipients such as lactose, starch, mannitol, dextrose, polylactic acid, polylactic acid-co-glycolide, and combinations thereof. A metered dose inhaler releases a measured amount of active agent using a compressed propellant gas. A typical metered formulation comprises a solution or suspension of the active agent in a liquefied propellant such as chlorofluorocarbon or hydrofluoroalkane. Optional components of such formulations include co-solvents such as ethanol or pentane, and surfactants such as sorbitan trioleate, oleic acid, lecithin, glycerin, and sodium lauryl sulfate. Such compositions are typically prepared by adding chilled or pressurized hydrofluoroalkane to a suitable container containing the active agent, ethanol (if present) and surfactant (if present). To prepare the suspension, the active agent is micronized and then combined with the propellant. Alternatively, suspension formulations can be prepared by spray drying a surfactant coating onto finely divided particles of the active agent. This formulation is then filled into an aerosol canister that forms part of the inhaler.

  The compounds of the present invention can also be administered parenterally (eg, subcutaneous, intravenous, intramuscular, or intraperitoneal injection). For such administration, the active agent is provided in a sterile solution, suspension, or emulsion. Typical solvents for preparing such formulations include water, saline, low molecular weight alcohols such as propylene glycol, polyethylene glycol, oils, gelatin, fatty acid esters such as ethyl oleate. Parenteral formulations may also contain one or more antioxidants, solubilizers, stabilizers, preservatives, wetting agents, emulsifying agents, and dispersing agents. Surfactants, additional stabilizers or pH adjusters (acids, bases or buffers) and antioxidants provide stability to the formulation, eg, hydrolysis of ester and amide bonds that may be present in the compound Is particularly useful in minimizing or avoiding. These formulations can be sterilized by use of a sterile injectable medium, sterilant, filtration, irradiation, or heat. In one particular embodiment, the parenteral formulation comprises an aqueous cyclodextrin solution as a pharmaceutically acceptable carrier. As a suitable cyclodextrin, a cyclic molecule containing 6 or more α-D-glucopyranose units linked at the 1,4 positions by linkage, as in amylase, β-cyclodextrin or cycloheptaamylose Is mentioned. Typical cyclodextrins include cyclodextrin derivatives such as hydroxypropyl cyclodextrin and sulfobutyl ether cyclodextrin such as hydroxypropyl-β-cyclodextrin and sulfobutyl ether β-cyclodextrin. Typical buffering agents for such formulations include carboxylic acid based buffers such as citrate buffer, lactate buffer and maleate buffer.

  The compounds of the present invention can also be administered transdermally using known transdermal delivery systems and excipients. For example, the compounds can be admixed with permeation enhancers such as propylene glycol, polyethylene glycol monolaurate, azacycloalkane-2-one, and incorporated into patches or similar delivery systems. If desired, additional excipients including gelling agents, emulsifiers and buffers can be used in such transdermal compositions.

Second Agent The compounds of the present invention may be useful as a single treatment for a disease or may be used in combination with one or more additional therapeutic agents to obtain the desired therapeutic effect. Accordingly, in one embodiment, the pharmaceutical compositions of the invention contain other drugs that are co-administered with the compounds of the invention. For example, the composition may further comprise one or more drugs (also referred to as “second agent (s)”). Such therapeutic agents are well known in the art and include adenosine receptor antagonists, α-adrenergic receptor antagonists, β ₁ -adrenergic receptor antagonists, β ₂ -adrenergic receptor agonists, dual acting β-adrenergic agents. Receptor antagonist / α ₁ -receptor antagonist, advanced glycation end product breaker, aldosterone antagonist, aldosterone synthase inhibitor, aminopeptidase N inhibitor, androgen, angiotensin converting enzyme inhibitor and dual acting angiotensin converting enzyme / neprilysin inhibitor , angiotensin-converting enzyme 2 activators and stimulators, angiotensin -II vaccine, an anticoagulant, antidiabetic agents, antidiarrheals, anti-glaucoma agents, anti-lipid agents, anti-nociceptive agents, antithrombotic agents, AT Receptor antagonists and dual-acting AT ₁ receptor antagonist / neprilysin inhibitors and multifunctional angiotensin receptor blockers, bradykinin receptor antagonists, calcium channel blockers, chymase inhibitors, digoxin, diuretics, dopamine agonists, endothelin Converting enzyme inhibitor, endothelin receptor antagonist, HMG-CoA reductase inhibitor, estrogen, estrogen receptor agonist and / or antagonist, monoamine reuptake inhibitor, muscle relaxant, natriuretic peptide and analogs thereof, natriuresis Peptide clearance receptor antagonist, neprilysin inhibitor, nitric oxide donor, non-steroidal anti-inflammatory agent, N-methyl d-aspartate receptor antagonist, o Oid receptor agonists, phosphodiesterase inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blockers, soluble guanylate cyclase stimulators and activators, three Cyclic antidepressants, vasopressin receptor antagonists, and combinations thereof. Specific examples of these agents are detailed herein.

  Accordingly, in yet another aspect of the invention, the pharmaceutical composition comprises a compound of the invention, a second active agent, and a pharmaceutically acceptable carrier. Third, fourth, etc. active agents may also be included in the composition. In combination therapy, the amount of the compound of the invention administered, as well as the amount of the second agent, may be less than the amount normally administered in monotherapy.

  The compounds of the present invention can also form a composition containing both agents by physical mixing with a second active agent, or each agent can be administered to a patient at the same time or at separate times. May be present in separate and different compositions. For example, a compound of the present invention can be a combination of active agents, including a compound of the present invention and a second active agent, in combination with a second active agent using conventional procedures and equipment. Can be formed. In addition, an active agent is used in combination with a pharmaceutically acceptable carrier to form a pharmaceutical composition comprising the compound of the present invention, a second active agent, and a pharmaceutically acceptable carrier. Can do. In this embodiment, the components of the composition are typically mixed or blended to create a physical mixture. The physical mixture is then administered in a therapeutically effective amount using any of the routes described herein.

  Alternatively, the active agents may remain separate and distinct before administration to the patient. In this embodiment, the agents are not physically mixed together prior to administration, but are administered as separate compositions at the same time or at different times. Such compositions can be packaged separately or can be packaged together in a kit. When administered at separate times, the second agent is used in a time shorter than 24 hours after administration of the compound of the present invention, i. At that time, it is usually administered. This is also called continuous administration. Thus, each active agent can be made into one tablet, two tablets can be used, and the compound of the invention can be orally administered together with another active agent, either simultaneously or sequentially, in which case sequential refers to the present invention Can be administered immediately after administration of the compound or after some pre-determined time (eg, 1 hour or 3 hours later). It is envisioned that the second agent may be administered more than 24 hours after administration of the compound of the present invention. Alternatively, the combination may be administered by different routes of administration, ie, one orally and the other by inhalation.

  In one embodiment, the kit comprises a first dosage form comprising a compound of the invention and at least one additional dosage form comprising one or more second agents described herein. In an amount sufficient to carry out the method of the invention. The first dosage form and the second (or third etc.) dosage form together comprise a therapeutically effective amount of the active agent for the treatment or prevention of a disease or medical condition in a patient.

  The second agent (s), if included, is present in a therapeutically effective amount such that when co-administered with a compound of the invention, they are normally administered in an amount that produces a therapeutically beneficial effect. To do. The second agent can be in the form of a pharmaceutically acceptable salt, solvate, optically pure stereoisomer, and the like. The second agent may also be in the form of a prodrug, such as a compound having an esterified carboxylic acid group. Accordingly, the second agents listed herein are intended to include all such forms and are commercially available or can be prepared using conventional procedures and reagents.

  In one embodiment, the compounds of the invention are administered in combination with an adenosine receptor antagonist. Representative examples of these include, but are not limited to, naxifylline, lorophilin, SLV-320, theophylline, and tonapophilin.

  In one embodiment, the compounds of the invention are administered in combination with an α-adrenergic receptor antagonist. Representative examples of these include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin.

The compounds of the present invention is also beta ₁ - can be administered in combination with an adrenergic receptor antagonist ( "beta ₁ blockers"). Representative beta ₁ blockers include, but are not limited to, acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befnolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucindolol, bucmolol, bufetrol, bufurolol, bunitrolol, bupranolol , Bubrizine, butofilolol, carazolol, carteolol, carvedilol, seriprolol, cetamol, chloranolol, direvalol, epanolol, esmolol, indenolol, labetrol, levobunolol, mepindolol, methypranolol, metoprolol succinate Moprolol, nadolol, nadoxolol, nebivalo , Nipradilol, oxprenolol, penbutolol, perbutolol, pindolol, practolol, pronetalol, propranolol, sotalol, sufinalol, tarindole, tertatrol, chirisolol, timolol, triprolol, xibenolol, and combinations thereof . In one particular embodiment, the β ₁ -antagonist is selected from atenolol, bisoprolol, metoprolol, propranolol, sotalol, and combinations thereof. Usually, the β ₁ blocker is administered in an amount sufficient to provide about 2-900 mg per dose.

In one embodiment, the compounds of the invention are administered in combination with a β ₂ -adrenergic receptor agonist. Representative examples of these include, but are not limited to, albuterol, vitorterol, fenoterol, formoterol, indacaterol, isoetarine, levalbuterol, metaproterenol, pyrbuterol, salbutamol, salmefamol, salmeterol, terbutaline, birantelol, etc. Is mentioned. Usually, the β ₂ -adrenergic receptor agonist is administered in an amount sufficient to provide about 0.05 to 500 μg per dose.

  In one embodiment, the compounds of the invention are administered in combination with an advanced glycation end product (AGE) breaker, examples of which include, but are not limited to, alagebrium (or ALT-711), and TRC4149 is mentioned.

  In another embodiment, the compounds of the invention are administered in combination with an aldosterone antagonist. Representative examples of these include, but are not limited to, eplerenone, spironolactone, and combinations thereof. Usually, the aldosterone antagonist is administered in an amount sufficient to provide about 5-300 mg per day.

  In one embodiment, the compounds of the invention are administered in combination with an aminopeptidase N or dipeptidyl peptidase III inhibitor, and these examples include, by way of illustration and not limitation, bestatin and PC18 (2-amino -4-methylsulfonylbutanethiol, methionine thiol).

The compounds of the present invention can also be administered in combination with an angiotensin converting enzyme (ACE) inhibitor. Representative ACE inhibitors include, but are not limited to, Akyupuriru, alacepril, benazepril, benazeprilat, captopril, ceranapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, Hoshinopurirato, imidapril, lisinopril, moexipril, Monopuriru, Mobell Ji prills, Pentopril, perindopril, quinapril, quinapril, ramipril, ramipril, salalacin acetate, spirapril, temocapril, trandolapril, zofenopril, and combinations thereof. In certain embodiments, the ACE inhibitor is selected from benazepril, captopril, enalapril, lisinopril, ramipril, and combinations thereof. Typically, the ACE inhibitor is administered in an amount sufficient to provide about 1-150 mg per day.

In another embodiment, the compounds of the invention are administered in combination with a dual acting angiotensin converting enzyme / neprilysin (ACE / NEP) inhibitor. Examples of these include, but are not limited to: AVE-0848 ((4S, 7S, 12bR) -7- [3-methyl-2 (S) -sulfanylbutyramide] -6-oxo-1 , 2,3,4,6,7,8,12b-octahydropyrido [2,1-a] [2] -benzazepine-4-carboxylic acid); AVE-7688 (Irepatril) and its parent compound; BMS-182657 (2- [2-oxo-3 (S)-[3-phenyl-2 (S) -sulfanylpropionamide] -2,3,4,5-tetrahydro-1H-1-benzazepine-1- Yl] acetic acid); CGS-26303 ([N- [2- (biphenyl-4-yl) -1 (S)-(1H-tetrazol-5-yl) ethyl] amino] methylphosphonic acid); CGS-356 1 (N- [1- [4-Methyl-2 (S) -sulfanylpentanamide] cyclopentylcarbonyl] -L-tryptophan); Fasidotolyl; -6- [3 (S) -methyl-2 (S) -sulfanylpentanamide] -5-oxoperhydrothiazolo [3,2-a] azepine-3-carboxylic acid); gem patrilato; MDL-101264 ((4S, 7S, 12bR) -7- [2 (S)-(2-morpholinoacetylthio) -3-phenylpropionamide] -6-oxo-1,2,3,4,6,7,8, 12b- octahydro pyrido [2,1-a] [2] benzazepine-4-carboxylic acid); MDL-101287 ([4S- [4α, 7α (R *), 2bβ]]-7- [2- (carboxymethyl) -3-phenylpropionamide] -6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido [2,1- a] [2] benzazepine-4-carboxylic acid); omapatrilato; RB-105 (N- [2 (S)-(mercaptomethyl) -3 (R) -phenylbutyl] -L-alanine); -898 ((2R, 4R) -N- [2- (2-hydroxyphenyl) -3- (3-mercaptopropionyl) thiazolidin-4-ylcarbonyl] -L-phenylalanine); Sch-50690 (N- [1 (S) -carboxy-2- [N2- (methanesulfonyl) -L-lysylamino] ethyl] -L-valyl-L-tyrosine); and combinations thereof may also be included. . In one particular embodiment, the ACE / NEP inhibitor is selected from AVE-7688, enalaprilate, faciditol, fasidotrilate, omapatrilato, sampatrilato, and combinations thereof.

  In one embodiment, the compounds of the invention are administered in combination with an angiotensin converting enzyme 2 (ACE2) activator or stimulant.

  In one embodiment, the compounds of the invention are administered in combination with an angiotensin-II vaccine. Examples of these include, but are not limited to, ATR12181 and CYT006-AngQb.

  In one embodiment, the compounds of the invention are administered in combination with an anticoagulant. Representative examples include, but are not limited to, coumarins such as warfarin; heparin; and direct thrombin inhibitors such as argatroban, bivalirudin, dabigatran, and repirudine.

  In yet another embodiment, the compounds of the invention are administered in combination with an antidiabetic agent. Exemplary anti-diabetic agents include injectable drugs and orally effective drugs, and combinations thereof. Examples of injectable drugs include, but are not limited to, insulin and insulin derivatives. Examples of orally effective drugs include, but are not limited to: biguanides such as metformin; glucagon antagonists; α-glucosidase inhibitors such as acarbose and miglitol; dipeptidyl peptidase IV inhibitors (DPP-IV inhibitors) ) Eg alogliptin, denagliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin; meglitinide, eg repaglinide, etc .; oxadiazolidinedione; And rosiglitazone; and combinations thereof.

In another embodiment, the compounds of the invention are administered in combination with an antidiarrheal treatment. As an alternative exemplary treatment, but are not limited to, oral rehydration beverage (ORS), loperamide, diphenoxylate, and subsalicylate bismuth scan the like.

In yet another embodiment, the compound of the invention is administered in combination with an anti-glaucoma agent. Representative anti-glaucoma agents include, but are not limited to: α-adrenergic agonists such as brimonidine; β ₁ -adrenergic receptor antagonists; topical β ₁ blockers such as betaxolol, levobunolol, and timolol; Ase inhibitors such as acetazolamide, brinzolamide, or dorzolamide; cholinergic agonists such as cevimeline and DMXB-anabasin; epinephrine compounds; miotic agents such as pilocarpine; and prostaglandin analogs.

  In yet another embodiment, the compounds of the invention are administered in combination with an antilipid agent. Representative antilipid agents include, but are not limited to, cholesteryl ester transfer protein inhibitors (CETP) such as anacetrapib, dalcetrapib, and torcetrapib; statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin; and these The combination of these is mentioned.

  In one embodiment, the compounds of the invention are administered in combination with an antithrombotic agent. Exemplary antithrombotic agents include, but are not limited to, aspirin; antiplatelet agents such as clopidogrel, prasugrel, and ticlopidine; heparin, and combinations thereof.

In one embodiment, the compounds of the invention are administered in combination with an AT ₁ receptor antagonist, also known as an angiotensin II type 1 receptor blocker (ARB). Representative ARBs include, but are not limited to, abitesartan, azilsartan (eg, azilsartan medoxomil), benzyl losartan, candesartan, candesartan cilexetil, erysartan, embusartan, enoltasosartan, eprosartan, EXP3174, vonsartan , Folasartan, glycyl losartan, irbesartan, isoteolin, losartan, medoxomil (medoximil), mifasartan (for example, olmesartan medoxomil), opomisartan, pratosartan, ripipsartan, saprisartan, salaracin, sarmesin, TAK-59, sarmesin, TAK-59 Telmisartan, valsartan, zolasartan, and combinations thereof. In certain embodiments, ARB is azilsartan medoxomil, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomil, Sa Purisarutan, tasosartan, telmisartan, is selected valsartan, and combinations thereof. Typical salts and / or prodrugs include candesartan cilexetil, eprosartan mesylate, losartan potassium salt, and olmesartan medoxomil. Usually, ARB is administered in an amount sufficient to provide about 4-600 mg per dose, with typical daily doses ranging from 20-320 mg per day.

The compounds of the present invention can also be administered in combination with dual acting agents such as AT ₁ receptor antagonist / neprilysin inhibitor (ARB / NEP) inhibitors, including but not limited to these , U.S. Publication Nos. 2008/0269305 and 2009/0023228 (both filed April 23, 2008 by Allegretti et al.), For example, the compound 4 ′-{2-ethoxy-4-ethyl -5-[((S) -2-mercapto-4-methylpentanoylamino) -methyl] imidazol-1-ylmethyl} -3'-fluorobiphenyl-2-carboxylic acid and the like.

  The compounds of the present invention may also be administered in combination with a multifunctional angiotensin receptor blocker as described in Kurtz & Klein (2009), Hypertension Research, 32: 826-834.

  In one embodiment, the compounds of the invention are administered in combination with a bradykinin receptor antagonist, such as icatibant (HOE-140). It is expected that this combination therapy can offer the advantage of preventing angioedema or other undesirable consequences of elevated bradykinin levels.

  In one embodiment, the compounds of the invention are administered in combination with a calcium channel blocker. Representative calcium channel blockers include, but are not limited to, amlodipine, anipamil, alanipin, valnidipine, benciclin, benidipine, bepridil, clentiazem, cilnidipine, cinnarizine, diltiazem, efonidipine, ergodipine, etaphenone, felodipine, fendiline, flunarizine, Galopamil, isradipine, rasidipine, lercanidipine, lerfradine, lidofrazine, lomerizine, manidipine, mibefradil, nicardipine, nifedipine, nigurdipine, nildipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, nivaldipine, perhexiline, preniramine, thiazilidine, preniramine, thiaziridine, The combination of these is mentioned. In certain embodiments, the calcium channel blocker is selected from amlodipine, bepridil, diltiazem, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigurdipine, nildipine, nimodipine, nisoldipine, riocidin, verapamil, and combinations thereof. Usually, the calcium channel blocker is administered in an amount sufficient to provide about 2-500 mg per dose.

  In one embodiment, the compounds of the invention are chymase inhibitors such as TPC-806 and 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N—. It is administered in combination with [{3,4-dioxo-1-phenyl-7- (2-pyridyloxy)}-2-heptyl] acetamide (NK3201) or the like.

In one embodiment, the compounds of the invention are administered in combination with a diuretic. Representative diuretics include, but are not limited to: carbonic anhydrase inhibitors, such as acetazolamide and dichlorphenamide Fe cyanamide; loop diuretics, which include sulfonamide derivatives such as acetazolamide, ambuside, Azose Mi de, bumetanide, Butazoramido, chlorambucil amino Fe cyanamide, Kurofenamido, clopamide, clorexolone, Jisurufamido, ethoxy key Suzorami de, furosemide, mefruside, methazolamide, piretanide, torsemide, tripamide, and xipamide the like; and non-sulfonamide diuretics, for example ethacrynic Acids and other phenoxyacetic acid compounds such as thienylic acid, indacrinone and quincalvert; osmotic diuretics such as mannitol; potassium-sparing diuretics, including aldosterone Down antagonists such spironolactone, and Na ⁺ channel inhibitors such as amiloride and triamterene and the like; thiazide and thiazide-like diuretics, for example althiazide, bendroflumethiazide, benzyl hydrochlorothiazide, benzo thiazides, Buchiajido, chlorthalidone, chlorothiazide, Cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenxone, flumethiazide, hydrochlorothiazide, hydroflumethiazide, indapamide, methylcrothiazide, methicrane, metolazone, paraflutidide, polythiazide, kinesazone, tecrothiazide, and combinations of trichloromethiazide; It is done. In certain embodiments, the diuretic is amiloride, bumetanide, chlorothiazide, chlorthalidone, dichlorphenamide, ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, methylclothiazide, metolazone, tolsemide, triamterene, and these Selected from the combinations. The diuretic is administered in an amount sufficient to provide about 5-50 mg per day, more usually 6-25 mg per day, with typical dosages being 6.25 mg, 12.5 mg or 25 mg per day. It is.

  The compounds of the present invention can also be administered in combination with an endothelin converting enzyme (ECE) inhibitor, examples of which include, but are not limited to, phosphoramidon, CGS2633, and combinations thereof.

  In certain embodiments, the compounds of the invention are administered in combination with an endothelin receptor antagonist. Exemplary endothelin receptor antagonists include, but are not limited to: selective endothelin receptor antagonists that affect endothelin A receptor, such as avosentan, ambrisentan, atrasentan, BQ-123, clazosentan, darsentan, sitaxentan, and As well as dual endothelin receptor antagonists that affect both endothelin A and B receptors, such as bosentan, macitentan, tezosentan and the like.

  In yet another embodiment, the compounds of the invention are administered in combination with one or more HMG-CoA reductase inhibitors, also known as statins. Exemplary statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

  In one embodiment, the compounds of the invention are administered in combination with a monoamine reuptake inhibitor and these examples include, by way of illustration and not limitation, norepinephrine reuptake inhibitors such as atomoxetine, buproprion and buproprion. Proprion metabolite hydroxybuproprion, maprotiline, reboxetine, and viloxazine; selective serotonin reuptake inhibitors (SSRI) such as citalopram and citalopram metabolite desmethyl citalopram, dapoxetine, escitalopram (eg escitalopram oxalate) and fluoxazine Fluoxetine desmethyl metabolite norfluoxetine, fluvoxamine (eg, fluvoxamine maleate), paroxetine, sertraline and celto Phosphorus metabolites demethylsertraline sertraline; dual serotonin - norepinephrine reuptake inhibitors (SNRI), for example bicifadine, duloxetine, milnacipran, nefazodone, and venlafaxine; is and combinations thereof and the like.

  In another embodiment, the compound of the invention is administered in combination with a muscle relaxant. Examples of these include, but are not limited to: carisoprodol, chlorzoxazone, cyclobenzaprine, diflunisal, metaxalone, metcarbamol, and combinations thereof.

  In one embodiment, the compounds of the invention are administered in combination with a natriuretic peptide or analog. Examples of these include, but are not limited to: carperitide, CD-NP (Nile therapy), CU-NP, nesiritide, PL-3994 (Palatin Technologies, Inc.), uralitide, sendelide, and Ogawa et al. (2004). J. et al. Biol. Chem. 279: 28625-page 31 are mentioned. These compounds are also called natriuretic peptide receptor-A (NPR-A) agonists. In another embodiment, a compound of the invention is a natriuretic peptide clearance receptor (NPR-C) antagonist such as SC-46542, cANF (4-23), and AP-811 (Veale (2000) Bioorg Med Chem. Lett., 10: 1949-52). For example, AP-811 shows a synergistic effect when used in combination with a NEP inhibitor, thiorphan (Wegner (1995) Clin. Expert. Hypert. 17: 861-876).

  In another embodiment, the compounds of the invention are administered in combination with a neprilysin (NEP) inhibitor. Representative NEP inhibitors include, but are not limited to: AHU-377; candoxatril; candoxatrilato; dexecadotolyl ((+)-N- [2 (R)-(acetylthiomethyl) -3-phenylpropionyl] Glycine benzyl ester); CGS-24128 (3- [3- (biphenyl-4-yl) -2- (phosphonomethylamino) propionamido] propionic acid); CGS-24592 ((S) -3- [3- (Biphenyl-4-yl) -2- (phosphonomethylamino) propionamido] propionic acid); CGS-25155 (N- [9 (R)-(acetylthiomethyl) -10-oxo-1-azacyclodecane) -2 (S) -ylcarbonyl] -4 (R) -hydroxy-L-proline benzyl ester); 3- (1-carbamo (Lucyclohexyl) propionic acid derivative (Pfizer Inc.) (described in Hepworth et al., WO 2006/027680); JMV-390-1 (2 (R) -benzyl-3- (N-hydroxycarbamoyl) propionyl-L-isoleucil-L -Leucine); ecadotolyl; phosphoramidon; retrothiorphan; RU-42827 (2- (mercaptomethyl) -N- (4-pyridinyl) benzenepropionamide); RU-44004 (N- (4-morpholinyl) -3-phenyl -2- (sulfanylmethyl) propionamide); SCH-32615 ((S) -N- [N- (1-carboxy-2-phenylethyl) -L-phenylalanyl] -β-alanine) and its prodrugs SCH-34826 ((S) -N- [N- 1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] carbonyl] -2-phenylethyl] -L-phenylalanyl] -β-alanine); sialorphine; SCH-42495 ( N- [2 (S)-(acetylsulfanylmethyl) -3- (2-methylphenyl) propionyl] -L-methionine ethyl ester); spinorphine; SQ-28132 (N- [2- (mercaptomethyl) -1 -Oxo-3-phenylpropyl] leucine); SQ- 28603 (N- [2- (mercaptomethyl) -1-oxo-3-phenylpropyl] -β-alanine); SQ-29072 (7-[[2- (Mercaptomethyl) -1-oxo-3-phenylpropyl] amino] heptanoic acid); thiorphan and its prodrugs, race UK-69578 (cis-4-[[[1- [2-carboxy-3- (2-methoxyethoxy) propyl] cyclopentyl] carbonyl] amino] cyclohexanecarboxylic acid); UK-447,841 (2- { 1- [3- (4-chlorophenyl) propylcarbamoyl] -cyclopentylmethyl} -4-methoxybutyric acid); UK-505,749 ((R) -2-methyl-3- {1- [3- (2-methyl) Benzothiazol-6-yl) propylcarbamoyl] cyclopentyl} propionic acid); 5-biphenyl-4-yl-4- (3-carboxypropionylamino) -2-methylpentanoic acid and 5-biphenyl-4-yl-4- (3-Carboxypropionylamino) -2-methylpentanoic acid ethyl ester (WO2007 / 0 6546); Daglutril [(3S, 2′R) -3- {1- [2 ′-(ethoxycarbonyl) -4′-phenylbutyl] -cyclopentane-1-carbonylamino} -2,3,4,5 -Tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid] (Novartis AG) (described in Khder et al., WO 2007/106708); and combinations thereof. In certain embodiments, the NEP inhibitor is selected from AHU-377, candoxatril, candoxatrilat, CGS-24128, phosphoramidon, SCH-32615, SCH-34826, SQ- 28603, thiorphan, and combinations thereof. The In certain embodiments, NEP inhibitors are compounds such as daglutril, which also have activity as inhibitors of both endothelin converting enzyme (ECE) and NEP. Other dual acting ECE / NEP compounds can also be used. The NEP inhibitor is administered in an amount sufficient to provide about 20-800 mg per day, the usual daily dose is in the range of 50-700 mg per day, more typically 100 per day. It is in the range of ~ 600 or 100-300 mg.

  In one embodiment, the compounds of the invention are administered in combination with a nitric oxide donor. Examples of these include, but are not limited to, nicorandil; organic nitrates such as pentaerythritol tetranitrate; and sydnonimines such as linsidomine and molsidomine.

In yet another embodiment, the compounds of the invention are administered in combination with a nonsteroidal anti-inflammatory agent (NSAID). Representative NSAID, but are not limited to: acemetacin, acetyl salicylic acid, alclofenac, alminoprofen, amfenac, Amipurirosu, A b Kishipurin, Aniroraku, apazone, azapropazone, benorylate, benoxaprofen, Bezupiperiron, Buroperamoru, Bukurokishin acid , Carprofen, clidanac, diclofenac, diflunisal, diphthalone, enolicam, etodolac, etlicoxib, fenbufen, fenclofenac, fenclozic acid, fenoprofen, fentiazak, feprazone, flufenamic acid, flufenisal, fluprofen, flurbiprofen, flurofenac, Ibufenac, ibuprofen, indomethacin, indoprofen, isoxepac, isoxy , Ketoprofen, ketorolac, lofemisol, lornoxicam, meclofenamate, meclofenamic acid, mefenamic acid, meloxicam, mesalamine, miloprofen, mofebutazone, nabumetone, naproxen, niflumic acid, oxaprozin, oxypinac, oxyphenbutazone, phenylbutazone, piroxicam , Pirprofen, pranoprofen, salsalate, sudoxicam, sulfasalazine, sulindac, suprofen, tenoxicam, thiopinac, thiaprofenic acid, thoxaprofen, tolfenamic acid, tolmetimid, triflumidate, didemetacin, zomepilac, and combinations thereof . In certain embodiments, the NSAID is selected from etodolac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam, naproxen, oxaprozin, piroxicam, and combinations thereof.

  In one embodiment, the compounds of the invention are administered in combination with an N-methyl d-aspartate (NMDA) receptor antagonist, examples of which include, by way of illustration and not limitation, amantadine, dextrose Examples include lometrphan, dextropropoxyphene, ketamine, ketobemidone, memantine, and methadone.

  In yet another embodiment, the compounds of the invention are administered in combination with an opioid receptor agonist (also referred to as an opioid analgesic). Representative opioid receptor agonists include, but are not limited to: buprenorphine, butorphanol, codeine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levalorphan, levorphanol, meperidine, methadone, morphine, nalbuphine, nalmefene, nalolphine, naloxone, Naltrexone, narolphine, oxycodone, oxymorphone, pentazocine, propoxyphene, tramadol, and combinations thereof. In certain embodiments, the opioid receptor agonist is selected from codeine, dihydrocodeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, tramadol, and combinations thereof.

  In certain embodiments, the compounds of the invention are administered in combination with a phosphodiesterase (PDE) inhibitor, particularly a PDE-V inhibitor. Exemplary PDE-V inhibitors include, but are not limited to, avanafil, rodenafil, milodenafil, sildenafil (Revatio®), tadalafil (Adcirca®), vardenafil (Levitra®), and Udenafil is mentioned.

  In another embodiment, the compounds of the invention are administered in combination with a prostaglandin analog (also referred to as a prostanoid or prostacyclin analog). Representative prostaglandin analogs include, but are not limited to, beraprost sodium, bimatoprost, epoprostenol, iloprost, latanoprost, tafluprost, travoprost, and treprostinil, and of particular interest are bimatoprost, latanoprost, and tafluprost. It is.

  In yet another embodiment, the compounds of the invention are administered in combination with a prostaglandin receptor agonist. Examples of these include, but are not limited to, bimatoprost, latanoprost, travoprost and the like.

  The compounds of the present invention may also be administered in combination with a renin inhibitor. Examples of these include, but are not limited to, aliskiren, enalkylene, remixylene, and combinations thereof.

  In another embodiment, the compounds of the invention are administered in combination with a selective serotonin reuptake inhibitor (SSRI). Representative SSRIs include, but are not limited to: citalopram and citalopram metabolite desmethyl citalopram, dapoxetine, escitalopram (eg, escitalopram oxalate), fluoxetine and fluoxetine desmethyl metabolite norfluoxetine, fluvoxamine maleate (eg, fluvoxamine maleate) , Paroxetine, sertraline and sertraline metabolite demethyl sertraline, and combinations thereof.

In one embodiment, the compounds of the invention are administered in combination with a 5-HT _1D serotonin receptor agonist, examples of which include, by way of illustration and not limitation, triptans such as almotriptan, abitriptan, Examples include eletriptan, frovatriptan, naratriptan rizatriptan, sumatriptan, and zolmitriptan.

In one embodiment, the compounds of the present invention is administered in combination with a sodium channel blocker, in these examples, as illustrated, without being limited to, carbamazepine, fosphenytoin, Ramotori di emissions, lidocaine, mexiletine, Oxcarbazepine, phenytoin, and combinations thereof.

  In one embodiment, the compounds of the invention are administered in combination with a soluble guanylate cyclase stimulant or activator. Examples of these include, but are not limited to, atashiguato, riociguato, and combinations thereof.

  In one embodiment, the compounds of the invention are administered in combination with a tricyclic antidepressant (TCA) and these examples include, by way of illustration and not limitation, amitriptyline, amitriptylinoxide, Buttriptyline, clomipramine, demexpitrine, desipramine, dibenzepin, dimethacrine, doslepine, doxepin, imipramine, imipraminoxide, lofepramine, melitracene, metapramine, nitrozazepine, nortriptyline, noxiptillin, pipeofezin, propipinepine, protriptyline, protriptyline, protriptyline, protriptyline Can be mentioned.

  In one embodiment, the compounds of the invention are administered in combination with a vasopressin receptor antagonist, examples of which include, but are not limited to, conivaptan and tolvaptan.

The second therapeutic agent used in combination can also be useful in further combination therapy with the compounds of the invention. For example, the compound of the present invention can be used in combination with a diuretic and ARB, or a calcium channel blocker and ARB, or a diuretic and ACE inhibitor, or a calcium channel blocker and a statin. Specific examples include the combination of the ACE inhibitor enalapril (maleate form) and the diuretic hydrochlorothiazide (sold under the mark Vaseetic®), or the calcium channel blocker amlodipine (besylate form) Examples include combinations of ARB olmesartan (medoxomil prodrug form) or calcium channel blockers and statins, all of which can be used with the compounds of the present invention. Other therapeutic agents such as α ₂ -adrenergic receptor agonists and vasopressin receptor antagonists may also be useful in combination therapy. Exemplary α ₂ -adrenergic receptor agonists include clonidine, dexmedetomidine, and guanfacine.

  The following formulations illustrate representative pharmaceutical compositions of the present invention.

Exemplary Hard Gelatin Capsule for Oral Administration A compound of the invention (50 g), 440 g spray dried lactose and 10 g magnesium stearate are thoroughly blended. The resulting composition is then filled into hard gelatin capsules (500 mg composition per capsule). Alternatively, a compound of the invention (20 mg) is thoroughly blended with starch (89 mg), microcrystalline cellulose (89 mg) and magnesium stearate (2 mg). The mixture is then passed through a US 45 mesh sieve and filled into hard gelatin capsules (200 mg composition per capsule).

  Alternatively, the compound of the invention (30 g), the second agent (20 g), 440 g spray dried lactose and 10 g magnesium stearate are thoroughly blended and processed as described above.

Exemplary Gelatin Capsule Formulation for Oral Administration A compound of the invention (100 mg) is thoroughly blended with polyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg). The mixture is then filled into gelatin capsules (400 mg composition per capsule). Alternatively, the compound of the invention (70 mg) and the second agent (30 mg) are thoroughly blended with polyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg) and the resulting mixture is filled into gelatin capsules (400 mg composition per capsule).

  Alternatively, a compound of the invention (40 mg) is thoroughly blended with microcrystalline cellulose (Avicel PH103; 259.2 mg) and magnesium stearate (0.8 mg). The mixture is then filled into gelatin capsules (size # 1, white, opaque) (300 mg composition per capsule).

Exemplary Tablet Formulation for Oral Administration The compound of the present invention (10 mg), starch (45 mg) and microcrystalline cellulose (35 mg) are passed through a US # 20 mesh sieve and mixed well. The granule thus produced is dried at 50 to 60 ° C. and passed through a 16 mesh US sieve. A polyvinylpyrrolidone solution (4 mg as a 10% solution in sterile water) is mixed with sodium carboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg), and talc (1 mg), and the mixture is then mixed with the United States. Pass through a 16 mesh screen. Then sodium carboxymethyl starch, magnesium stearate and talc are added to the granules. After mixing, the mixture is compressed on a tablet machine to produce a tablet weighing 100 mg.

  Alternatively, the compound of the invention (250 mg) is thoroughly blended with microcrystalline cellulose (400 mg), fumed silicon dioxide (10 mg), and stearic acid (5 mg). The mixture is then compressed to form tablets (665 mg composition per tablet).

  Alternatively, a compound of the invention (400 mg) is thoroughly blended with corn starch (50 mg), croscarmellose sodium (25 mg), lactose (120 mg), and magnesium stearate (5 mg). The mixture is then compressed to form a single split tablet (composition 600 mg per tablet).

  Alternatively, a compound of the invention (100 mg) is thoroughly blended with corn starch (100 mg) and an aqueous gelatin (20 mg) solution. The mixture is dried and ground to a fine powder. Microcrystalline cellulose (50 mg) and magnesium stearate (5 mg) are then mixed with the gelatin formulation, granulated, and the resulting mixture is compressed to form tablets (100 mg of the compound of the invention per tablet).

Typical Suspension Formulation for Oral Administration The following ingredients are mixed to form a suspension containing 100 mg of the compound of the invention per 10 mL of suspension.

典型的な経口投与用液体製剤
適切な液体製剤は、カルボン酸ベースの緩衝剤、例えばクエン酸緩衝液、乳酸緩衝液およびマレイン酸緩衝液などを用いたものである。例えば、本発明の化合物（ＤＭＳＯと予備混合しておいてもよい）を、１００ｍＭクエン酸アンモニウム緩衝剤とブレンドし、ｐＨをｐＨ５に調整するか、または１００ｍＭクエン酸溶液とブレンドし、ｐＨをｐＨ２に調整する。このような溶液はまた、シクロデキストリンなどの可溶化賦形剤を含んでもよく、例えば溶液は、１０重量％のヒドロキシプロピル−β−シクロデキストリンを含んでもよい。

Typical Liquid Formulations for Oral Administration Suitable liquid formulations are those using carboxylic acid based buffers such as citrate buffer, lactate buffer and maleate buffer. For example, a compound of the present invention (which may be premixed with DMSO) is blended with 100 mM ammonium citrate buffer and the pH is adjusted to pH 5 or blended with 100 mM citric acid solution to adjust the pH to pH 2 Adjust to. Such a solution may also contain a solubilizing excipient such as cyclodextrin, for example the solution may contain 10% by weight of hydroxypropyl-β-cyclodextrin.

Other suitable formulations include 5% NaHCO ₃ solution with or without cyclodextrin.

Exemplary Injectable Formulation for Administration by Injection A compound of the invention (0.2 g) is blended with 0.4 M sodium acetate buffer (2.0 mL). If necessary, adjust the pH of the resulting solution to pH 4 using 0.5N aqueous hydrochloric acid or 0.5N aqueous sodium hydroxide, and then add enough water for injection to total Bring volume to 20 mL. The mixture is then filtered through a sterile filter (0.22 micron) to provide a sterile solution suitable for administration by injection.

Exemplary Composition for Administration by Inhalation A compound of the invention (0.2 mg) is micronized and then blended with lactose (25 mg). The blended mixture is then filled into a gelatin inhalation cartridge. The contents of the cartridge are administered using, for example, a dry powder inhaler.

  Alternatively, the finely divided compound of the invention (10 g) is dispersed in a solution prepared by dissolving lecithin (0.2 g) in demineralized water (200 mL). The resulting suspension is spray dried and then micronized to form a micronized composition comprising particles having an average diameter of less than about 1.5 μm. The micronized composition is then pressurized 1,1,1,2-tetrafluoro in an amount sufficient to provide about 10 μg to about 500 μg of the compound of the invention per dose when administered by inhaler. Fill a metered dose inhaler cartridge containing ethane.

  Alternatively, the compound of the invention (25 mg) is dissolved in citrate buffered (pH 5) isotonic saline (125 mL). The mixture is stirred and sonicated until the compound is dissolved. Check the pH of the solution and adjust to pH 5 if necessary by slowly adding aqueous 1N NaOH. The solution is administered using a nebulizer device, which provides from about 10 μg to about 500 μg of the compound of the invention per dose.

  The following preparations and examples are provided to illustrate certain embodiments of the invention. However, these specific embodiments are not intended to limit the scope of the invention in any way unless specifically noted.

  The following abbreviations have the following meanings unless otherwise indicated, and any other abbreviations not used and defined herein are those standard and generally accepted meanings: Have

AcOH acetic acid (Boc) ₂ O di-t-butyl dicarbonate DCC dicyclohexylcarbodiimide DCM dichloromethane or methylene chloride DIBAL diisobutylaluminum hydride DIPEA N, N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N, N-dimethylformamide DMSO dimethyl sulfoxide Dnp 2,4-dinitrophenyl EDCI N- (3-dimethylaminopropyl) -N′-ethylcarbodiimide Et ₃ N triethylamine Et ₂ O diethyl ether EtOAc ethyl acetate EtOH ethanol HATU N, N, N ′, N′-tetramethyl -O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate HCTU (2- (6-chloro-1H-benzo Zotoriazoru-1-yl) -1,1,3,3-tetramethyl-aminium (Tetramethylaminium) hexafluorophosphate)
HEPES 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid HOAt 1-hydroxy-7-azabenzotriazole LiHMDS lithium hexamethyldisilazide Mca (7-methoxycoumarin-4-yl) acyl MeCN acetonitrile MeOH methanol Pd (PPh ₃ ) ₄ Tetrakis (triphenylphosphine) palladium (0)
SilicaCat® DPP-Pd Silica-based diphenylphosphine palladium (II) catalyst SilicaCat® Pd (0) Silica-based palladium (0) catalyst TFA trifluoroacetic acid THF tetrahydrofuran.

  Unless otherwise indicated, all materials, such as reagents, starting materials and solvents, were purchased from commercial suppliers (eg, Sigma-Aldrich, Fluka Riedel-de Haen, etc.) and used without further purification.

Unless otherwise indicated, reactions were performed under a nitrogen atmosphere. The progress of the reaction is monitored by thin layer chromatography (TLC), analytical high performance liquid chromatography (analytical HPLC), and mass spectrometry, the details of which are given in the specific examples. The solvents used in analytical HPLC were as follows:
Solvent A was 98% H ₂ O / 2% MeCN / 1.0 mL / L TFA; Solvent B was 90% MeCN / 10% H ₂ O / 1.0 mL / L TFA.

Work-up of the reaction was performed as specifically described in each preparation. For example, the reaction mixture was generally purified by extraction and other purification methods, such as temperature-dependent and solvent-dependent crystallization and precipitation. In addition, the reaction mixture was purified routinely by preparative HPLC, usually using Microsorb C18 and Microsorb BDS column packing materials and conventional eluents. The progress of the reaction was usually measured by liquid chromatography mass spectrometry (LCMS). The isomers were characterized by nuclear overhauser effect spectroscopy (NOE). The reaction products were characterized as specified by mass spectrometry and ¹ H-NMR spectroscopy. For NMR measurements, samples were dissolved in deuterated solvents (CD ₃ OD, CDCl ₃ , or DMSO-d ₆ ) and ¹ H-NMR using a Varian Gemini 2000 instrument (400 MHz) under standard observation conditions. A spectrum was acquired. Identification of compounds by mass spectrometry was typically performed using an electrospray ionization method (ESMS) using an Applied Biosystems (Foster City, CA) model API 150EX instrument or an Agilent (Palo Alto, Calif.) Model 1200 LC / MSD instrument. .

Preparation 1
Oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide)
MoO ₃ → MoO ₅ · H ₂ O · (Me ₂ N) ₃ PO → MoO ₅ · (Me ₂ N) ₃ PO → MoO ₅ · Py · (Me ₂ N) ₃ PO
Molybdenum oxide (MoO ₃ ; 30 g, 0.2 mol) and 30% hydrogen peroxide (150 mL) were mixed with stirring. The reaction vessel was placed in an oil bath equilibrated at 40 ° C. and heated until the internal temperature reached 35 ° C. The heating bath was then removed and replaced with a water bath to control a mild exothermic reaction so that an internal temperature of 35-40 ° C. was maintained. After an initial exothermic period (about 30 minutes), the reaction vessel is returned to the 40 ° C. oil bath and stirred for a total of 3.5 hours to form a yellow solution with a small amount of suspended white solid. did. After cooling to 20 ° C., the solution was filtered and the resulting yellow filtrate was cooled to 10 ° C. (with stirring in an ice bath) and hexamethylphosphoric triamide ((Me ₂ N) ₃ PO; HMPA; 37.3 g , 0.2 mol) was added dropwise over 5 minutes, resulting in the formation of a crystalline yellow precipitate. Stirring was continued at 10 ° C. for a total of 15 minutes and the product was filtered and compressed to dryness. After 30 minutes under vacuum, the filter cake was mixed with MeOH (20 mL) and stirred at 40 ° C. Additional MeOH was added slowly until the solid dissolved. When the saturated solution was cooled in the refrigerator, a yellow solid was formed (looked like a needle). The solid mass was physically broken, filtered and washed with cold MeOH (20-30 mL) to give oxodiperoxymolybdenum (aqua) (hexamethyl phosphate triamide) (MoO ₅ .H ₂ O.HMPA, 46-50 g).

MoO ₅ .H ₂ O.HMPA was dried over phosphorous oxide at 0.2 mmHg for 24 hours in a light-shielded vacuum desiccator to give a somewhat hygroscopic yellow solid, MoO ₅ .HMPA. Any precipitate was removed by dissolving MoO5 HMPA (36.0 g, 0.1 mol) in THF (150 mL) and filtering the solution. The filtrate was then stirred at 20 ° C. while dry pyridine (8.0 g, 0.1 mol) was added over 10 minutes. A crystalline, yellow product was collected, washed with dry THF (25 mL) and anhydrous ether (200 mL), and dried in a vacuum desiccator (1 hour, 0.2 mmHg) to give a finely divided yellow The title compound, oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) (MoO ₅ · Py · HMPA) was obtained as a solid (36-38 g).

Preparation 2
(S) -2-Biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t-butyl ester

無水ＤＣＭ（５００ｍＬ）中の（Ｒ）−３−ビフェニル−４−イル−２−ｔ−ブトキシカルボニルアミノプロピオン酸（５０ｇ、１４６．５ｍｍｏｌ）、メルドラム酸（２３．３ｇ、１６１．１ｍｍｏｌ）およびＤＭＡＰ（２７．８ｇ、２２７ｍｍｏｌ）の撹拌溶液に、ＤＣＣ（３３．３ｇ、１６１．１ｍｍｏｌ）の無水ＤＣＭ（２００ｍＬ）溶液を窒素下で、−５℃で１時間にわたり加えた。この混合物を−５℃で８時間撹拌し、次いで一晩冷蔵し、この間に、極めて小さな結晶のジシクロヘキシル尿素が沈殿した。濾過後、この混合物を５％ＫＨＳＯ_４（４×２００ｍＬ）、飽和水性ＮａＣｌ（１×２００ｍＬ）で洗浄し、ＭｇＳＯ_４で一晩乾燥させた。得られた溶液を蒸発させることによって、淡黄色の固体として粗製の化合物１を得た（６８ｇ）。ＬＣ−ＭＳ：［Ｍ^＋Ｎａ］：４９０、［２Ｍ^＋Ｎａ］：９５７。

(R) -3-Biphenyl-4-yl-2-tert-butoxycarbonylaminopropionic acid (50 g, 146.5 mmol), Meldrum acid (23.3 g, 161.1 mmol) and DMAP (in anhydrous DCM (500 mL)) To a stirred solution of 27.8 g, 227 mmol) was added a solution of DCC (33.3 g, 161.1 mmol) in anhydrous DCM (200 mL) at −5 ° C. over 1 hour under nitrogen. The mixture was stirred at −5 ° C. for 8 hours and then refrigerated overnight during which time very small crystals of dicyclohexylurea precipitated. After filtration, the mixture was washed with 5% KHSO ₄ (4 × 200 mL), saturated aqueous NaCl (1 × 200 mL) and dried over MgSO ₄ overnight. The resulting solution was evaporated to give crude compound 1 as a pale yellow solid (68 g). LC-MS: [M ⁺ Na]: 490, [2M ⁺ Na]: 957.

粗製の化合物１（６８ｇ、１４６．５ｍｍｏｌ）の無水ＤＣＭ（１０００ｍＬ）溶液に、窒素下で、−５℃でＡｃＯＨ（９６．８ｇ、１．６モル）を加えた。得られた混合物を−５℃で０．５時間撹拌し、次いでＮａＢＨ_４（１３．９ｇ、３６６ｍｍｏｌ）を少量ずつ２時間にわたり加えた。もう１時間−５℃で撹拌後、飽和水性ＮａＣｌ（３００ｍＬ）を加えた。有機層を、飽和水性ＮａＣｌ（２×３００ｍＬ）で洗浄し、次いで水（２×３００ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、蒸発させることによって、粗製の化合物２を得た。これをさらにクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝５：１）で精製することによって、淡黄色の固体として、精製された化合物２を得た（４６ｇ）。ＬＣ−ＭＳ：［Ｍ^＋Ｎａ］：４７６、［２Ｍ^＋Ｎａ］：９２９。

To a solution of crude compound 1 (68 g, 146.5 mmol) in anhydrous DCM (1000 mL) was added AcOH (96.8 g, 1.6 mol) at −5 ° C. under nitrogen. The resulting mixture was stirred at −5 ° C. for 0.5 hour, then NaBH ₄ (13.9 g, 366 mmol) was added in portions over 2 hours. After stirring for another hour at −5 ° C., saturated aqueous NaCl (300 mL) was added. The organic layer was washed with saturated aqueous NaCl (2 × 300 mL) and then with water (2 × 300 mL), dried over MgSO ₄ , filtered and evaporated to give crude compound 2. This was further purified by chromatography (hexane: EtOAc = 5: 1) to give purified compound 2 as a pale yellow solid (46 g). LC-MS: [M ⁺ Na]: 476, [2M ⁺ Na]: 929.

無水トルエン（３００ｍＬ）中の精製された化合物２（４６ｇ、１０１ｍｍｏｌ）の撹拌溶液を窒素下で３時間加熱還流した。溶媒の蒸発後、残渣をクロマトグラフィーで（ヘキサン：ＥｔＯＡｃ＝１０：１）で精製することによって、淡黄色の固体として、表題化合物を得た（２７ｇ）。

A stirred solution of purified compound 2 (46 g, 101 mmol) in anhydrous toluene (300 mL) was heated to reflux under nitrogen for 3 hours. After evaporation of the solvent, the residue was purified by chromatography (hexane: EtOAc = 10: 1) to give the title compound as a pale yellow solid (27 g).

^{LC-MS: [M + Na} ]: 374, [2M + Na]: 725; 1H NMR (300 MHz, CDCl 3): δ7.64-7.62 (m, 4H), 7.51-7.46 (M, 2H), 7.42-7.39 (m, 1H), 7.39-7.30 (m, 2H), 4.50-4.43 (m, 1H), 3.27-3 .89 (m, 1H), 2.88-2.80 (m, 1H), 2.48-2.42 (m, 2H), 2.09-1.88 (m, 2H), 1.66 (S, 9H).

Preparation 3
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester and (2R, 4S) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester ester

ステップ１：無水ＴＨＦ（７０ｍＬ）中の（Ｓ）−２−ビフェニル−４−イルメチル−５−オキソピロリジン−１−カルボン酸ｔ−ブチルエステル（４．４ｇ、１２．４ｍｍｏｌ）の撹拌溶液に、１Ｍ ＬｉＨＭＤＳのＴＨＦ（２８ｍＬ）溶液を、窒素下、−６５℃で１５分間にわたり加えた。３時間−６５℃で撹拌後、オキソジペルオキシモリブデン（ピリジン）（ヘキサメチルリン酸トリアミド）（９ｇ、１８．６ｍｍｏｌ）を加えた。この混合物を−３５℃でもう２時間撹拌し、次いで飽和水性Ｎａ_２Ｓ_２Ｏ_３（６０ｍＬ）を加えた。有機層を収集し、飽和水性ＮＨ_４Ｃｌ（６０ｍＬ×３）で洗浄し、飽和水性ＮａＣｌ（６０ｍＬ×２）で洗浄し、次いでＮａ_２ＳＯ_４で乾燥させ、溶媒を減圧下で除去することによって、粗生成物を得た。これをさらにクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝５：１）で精製することによって、白色の固体として、化合物１を得た（１．８ｇ）。ＬＣ−ＭＳ：［２Ｍ＋Ｎａ］：７５７。

Step 1: To a stirred solution of (S) -2-biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t-butyl ester (4.4 g, 12.4 mmol) in anhydrous THF (70 mL) was added 1M. LiHMDS in THF (28 mL) was added over 15 min at −65 ° C. under nitrogen. After stirring for 3 hours at −65 ° C., oxodiperoxymolybdenum (pyridine) (hexamethylphosphoric triamide) (9 g, 18.6 mmol) was added. The mixture was stirred at −35 ° C. for another 2 hours and then saturated aqueous Na ₂ S ₂ O ₃ (60 mL) was added. The organic layer was collected, washed with saturated aqueous NH ₄ Cl (60 mL × 3), washed with saturated aqueous NaCl (60 mL × 2), then dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The crude product was obtained. This was further purified by chromatography (hexane: EtOAc = 5: 1) to give compound 1 as a white solid (1.8 g). LC-MS: [2M + Na]: 757.

ステップ２：化合物１（１．８ｇ、５．０ｍｍｏｌ）の無水ＤＣＭ（５０ｍＬ）溶液に、窒素下、０℃で、ＤＭＡＰ（１２２ｍｇ、１ｍｍｏｌ）およびＥｔ_３Ｎ（１．５ｇ、１４．９ｍｍｏｌ）を加えた。０℃で０．５時間撹拌後、塩化ベンジル（１．０ｇ、７．４ｍｍｏｌ）を１５分間にわたり加えた。この混合物を０℃でさらに２時間撹拌し、次いで飽和水性ＮａＨＣＯ_３（５０ｍＬ）を加えた。有機層を収集し、飽和水性ＮａＨＣＯ_３（５０ｍＬ×２）で洗浄し、飽和水性ＮａＣｌ（５０ｍＬ×１）で洗浄し、次いでＮａ_２ＳＯ_４で乾燥させた。固体を濾過して除き、濾液を濃縮することによって、粗生成物を得た。これをクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝４：１）でさらに精製することによって、白色の固体として、化合物２Ａ（４７１ｍｇ）および化合物２Ｂ（８８３ｍｇ）を得た。ＬＣ−ＭＳ：［Ｍ＋Ｎａ］：４９４；［２Ｍ＋Ｎａ］：９６５。
化合物２Ａ：^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤＣｌ_３）： δ （ｐｐｍ） ＝８．０２ （ｍ，２Ｈ）， ７．５７−７．２５ （ｍ，１２Ｈ）， ５．４２ （ｍ，１Ｈ）， ４．５０ （ｍ，１Ｈ）， ３．２６−３．２１ （ｍ， １Ｈ）， ２．９０ （ｍ， １Ｈ）， ２．５８ （ｍ， １Ｈ）， ２．１５−２．０５ （ｍ， １Ｈ）， １．６２ （ｍ，９Ｈ）。
化合物２Ｂ：^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤＣｌ_３）： δ （ｐｐｍ） ＝８．０６ （ｍ，２Ｈ）， ７．５８−７．１８ （ｍ，１２Ｈ）， ５．５３−５．４１ （ｍ，１Ｈ）， ４．３９ （ｍ，１Ｈ）， ３．５７−３．５４ （ｍ， １Ｈ）， ２．８７−２．８０ （ｍ， １Ｈ）， ２．４８−２．４４ （ｍ， １Ｈ），１．９８ （ｍ， １Ｈ）， １．６３ （ｍ，９Ｈ）。

Step 2: To a solution of compound 1 (1.8 g, 5.0 mmol) in anhydrous DCM (50 mL) at 0 ° C. under nitrogen was added DMAP (122 mg, 1 mmol) and Et ₃ N (1.5 g, 14.9 mmol). added. After stirring at 0 ° C. for 0.5 hour, benzyl chloride (1.0 g, 7.4 mmol) was added over 15 minutes. The mixture was stirred at 0 ° C. for a further 2 hours and then saturated aqueous NaHCO ₃ (50 mL) was added. The organic layer was collected, washed with saturated aqueous NaHCO ₃ (50 mL × 2), washed with saturated aqueous NaCl (50 mL × 1), and then dried over Na ₂ SO ₄ . The solid was filtered off and the filtrate was concentrated to give the crude product. This was further purified by chromatography (hexane: EtOAc = 4: 1) to give Compound 2A (471 mg) and Compound 2B (883 mg) as white solids. LC-MS: [M + Na]: 494; [2M + Na]: 965.
Compound 2A: ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.02 (m, 2H), 7.57-7.25 (m, 12H), 5.42 (m, 1H), 4.50 (m, 1H), 3.26-3.21 (m, 1H), 2.90 (m, 1H), 2.58 (m, 1H), 2.15-2.05 (m, 1H), 1.62 (m, 9H).
Compound 2B: ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.06 (m, 2H), 7.58-7.18 (m, 12H), 5.53-5.41 (m , 1H), 4.39 (m, 1H), 3.57-3.54 (m, 1H), 2.87-2.80 (m, 1H), 2.48-2.44 (m, 1H) ), 1.98 (m, 1H), 1.63 (m, 9H).

ステップ３：無水ＥｔＯＨ（１０ｍＬ）中の化合物２Ａ（４７１ｍｇ、１ｍｍｏｌ）の撹拌溶液に、窒素下、室温で無水Ｋ_２ＣＯ_３（６９１ｍｇ、５ｍｍｏｌ）を加えた。室温で２０時間撹拌後、固体を濾過して除いた。濾液に、水（３０ｍＬ）、ＤＣＭ（３０ｍＬ）および飽和水性ＮａＣｌ（５ｍＬ）を加えた。水層を分離し、ＤＣＭ（３０ｍＬ×３）で抽出した。合わせた有機層を飽和水性ＮａＣｌ（５０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮することによって、粗生成物を得た。これをクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝６：１）でさらに精製することによって、白色の固体として、化合物３を得た（２７５ｍｇ）。ＬＣ−ＭＳ：［Ｍ＋Ｎａ］：４３６、［２Ｍ＋Ｎａ］：８４９。

Step 3: To a stirred solution of compound 2A (471 mg, 1 mmol) in anhydrous EtOH (10 mL) was added anhydrous K ₂ CO ₃ (691 mg, 5 mmol) at room temperature under nitrogen. After stirring at room temperature for 20 hours, the solid was removed by filtration. To the filtrate was added water (30 mL), DCM (30 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was separated and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over Na ₂ SO ₄ and concentrated to give the crude product. This was further purified by chromatography (hexane: EtOAc = 6: 1) to give compound 3 (275 mg) as a white solid. LC-MS: [M + Na]: 436, [2M + Na]: 849.

ステップ４：ＥｔＯＨ（５ｍＬ）に、−３０℃で塩化アセチル（６８５ｍｇ）を加えた。−３０℃で１時間撹拌後、化合物３（２７５ｍｇ、６６５μｍｏｌ）の無水ＥｔＯＨ（５ｍＬ）溶液を加えた。この混合物を２５℃に加熱し、２５℃で３時間撹拌した。溶媒の蒸発後、残渣を冷たい無水Ｅｔ_２Ｏ（１０ｍＬ）で洗浄することによって、白色固体のＨＣｌ塩として、（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステルを得た（２０７ｍｇ）。ＬＣ−ＭＳ：［Ｍ＋Ｈ］：３１４、［２Ｍ＋Ｎａ］：６４９。
^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤＣｌ_３）： δ （ｐｐｍ） ＝７．９９ （ｍ，３Ｈ）， ７．６６−７．６４ （ｍ，４Ｈ）， ７．４８−７．３５ （ｍ，５Ｈ）， ６．０８ （ｍ，１Ｈ）， ４．２１ （ｍ，１Ｈ）， ４．０９−４．０５ （ｍ， ２Ｈ）， ３．５２ （ｍ， １Ｈ）， ２．９７−２．９５ （ｍ， ２Ｈ）， １．８９−１．８７ （ｍ， ２Ｈ）， １．１９−１．１４ （ｍ，３Ｈ）。

Step 4: Acetyl chloride (685 mg) was added to EtOH (5 mL) at −30 ° C. After stirring at −30 ° C. for 1 hour, a solution of compound 3 (275 mg, 665 μmol) in absolute EtOH (5 mL) was added. The mixture was heated to 25 ° C. and stirred at 25 ° C. for 3 hours. After evaporation of the solvent, the residue was washed with cold anhydrous Et ₂ O (10 mL) to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentane as a white solid HCl salt. The acid ethyl ester was obtained (207 mg). LC-MS: [M + H]: 314, [2M + Na]: 649.
¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 7.99 (m, 3H), 7.66-7.64 (m, 4H), 7.48-7.35 (m, 5H) , 6.08 (m, 1H), 4.21 (m, 1H), 4.09-4.05 (m, 2H), 3.52 (m, 1H), 2.97-2.95 (m , 2H), 1.89-1.87 (m, 2H), 1.19-1.14 (m, 3H).

ステップ５：無水ＥｔＯＨ（１５ｍＬ）中の化合物２Ｂ（８８３ｍｇ、１．９ｍｍｏｌ）の撹拌溶液に、窒素下、室温で、無水Ｋ_２ＣＯ_３（１２９３ｍｇ、９．４ｍｍｏｌ）を加えた。室温で２０時間撹拌後、固体を濾過して除いた。濾液に水（３０ｍＬ）、ＤＣＭ（３０ｍＬ）および飽和水性ＮａＣｌ（５ｍＬ）を加えた。水層を分離し、ＤＣＭ（３０ｍＬ×３）で抽出した。合わせた有機層を飽和水性ＮａＣｌ（５０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮することによって、粗生成物を得た。これをクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝６：１）でさらに精製することによって、白色の固体として、化合物４を得た（５２４ｍｇ）。ＬＣ−ＭＳ：［Ｍ＋Ｎａ］：４３６、［２Ｍ＋Ｎａ］：８４９。

Step 5: Anhydrous EtOH (15 mL) compounds in 2B (883 mg, 1.9 mmol) to a stirred solution under nitrogen at room temperature was added anhydrous _{K 2 CO 3 (1293mg, 9.4mmol} ). After stirring at room temperature for 20 hours, the solid was removed by filtration. To the filtrate was added water (30 mL), DCM (30 mL) and saturated aqueous NaCl (5 mL). The aqueous layer was separated and extracted with DCM (30 mL × 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over Na ₂ SO ₄ and concentrated to give the crude product. This was further purified by chromatography (hexane: EtOAc = 6: 1) to give compound 4 as a white solid (524 mg). LC-MS: [M + Na]: 436, [2M + Na]: 849.

ステップ６：ＥｔＯＨ（８ｍＬ）に、−３０℃で塩化アセチル（１３００ｍｇ）を加えた。−３０℃で１時間撹拌後、化合物４（５２４ｍｇ、１．３ｍｍｏｌ）の無水ＥｔＯＨ（８ｍＬ）溶液を加えた。この混合物を２５℃で加熱し、２５℃で３時間撹拌した。溶媒の蒸発後、残渣を冷たい無水Ｅｔ_２Ｏ（１０ｍＬ）で洗浄することによって、白色固体のＨＣｌ塩として、（２Ｒ，４Ｓ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステルを得た（３９５ｍｇ）。ＬＣ−ＭＳ：［Ｍ＋Ｈ］：３１４、［２Ｍ＋Ｎａ］：６４９。
^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＣＤＣｌ_３）： δ （ｐｐｍ） ＝８．１４ （ｍ，３Ｈ）， ７．６６−７．６２ （ｍ，４Ｈ）， ７．４７−７．３１ （ｍ，５Ｈ）， ５．８７−５．８５ （ｍ，１Ｈ）， ４．３４ （ｍ，１Ｈ）， ４．０８−４．００ （ｍ， ２Ｈ）， ３．４８ （ｍ， １Ｈ）， ３．０９ （ｍ， １Ｈ）， ２．８５−２．８１ （ｍ， １Ｈ）， １．８８（ｍ，１Ｈ）， １．７６ （ｍ，１Ｈ）， １．１５−１．１０ （ｍ，３Ｈ）。

Step 6: Acetyl chloride (1300 mg) was added to EtOH (8 mL) at -30 ° C. After stirring at −30 ° C. for 1 hour, a solution of compound 4 (524 mg, 1.3 mmol) in absolute EtOH (8 mL) was added. The mixture was heated at 25 ° C. and stirred at 25 ° C. for 3 hours. After evaporation of the solvent, the residue was washed with cold anhydrous Et ₂ O (10 mL) to give (2R, 4S) -4-amino-5-biphenyl-4-yl-2-hydroxypentane as a white solid HCl salt. The acid ethyl ester was obtained (395 mg). LC-MS: [M + H]: 314, [2M + Na]: 649.
¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) = 8.14 (m, 3H), 7.66-7.62 (m, 4H), 7.47-7.31 (m, 5H) , 5.87-5.85 (m, 1H), 4.34 (m, 1H), 4.08-4.00 (m, 2H), 3.48 (m, 1H), 3.09 (m , 1H), 2.85-2.81 (m, 1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.15-1.10 (m, 3H).

  Alternative synthesis of (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester

［（Ｓ）−２−ビフェニル−４−イル−１−（２，２−ジメチル−４，６−ジオキソ−［１，３］ジオキサン−５−イルメチル）エチル］−カルバミン酸ｔ−ブチルエステル（１４３ｇ、３２０ｍｍｏｌ）の無水トルエン（１Ｌ）溶液を、窒素下で一晩、加熱還流した。溶媒を減圧下で除去することによって、（Ｓ）−２−ビフェニル−４−イルメチル−５−オキソピロリジン−１−カルボン酸ｔ−ブチルエステルを得た。これをさらなる精製なしでそのまま使用し、ＥｔＯＡｃ（１．２Ｌ）中の３Ｎ ＨＣｌの溶液に加えた。生成した混合物を室温で３時間撹拌した。溶媒を真空中で除去した。残渣をＥｔＯＡｃ（３００ｍＬ）中で再結晶化することによって、第１のバッチの脱保護された化合物を得た（５６ｇ）。母液をクロマトグラフィーカラム（ＥｔＯＡｃおよびヘキサン、１：１〜１００％ＥｔＯＡｃで溶出）にかけることによって、第２のバッチの脱保護した化合物を得た（８ｇ）。脱保護した化合物（６４ｇ、２５０ｍｍｏｌ）の無水ＴＨＦ（５００ｍＬ）中懸濁液に、ＢｕＬｉ（１００ｍＬ、ヘキサン中２．５Ｍ）を−７８℃で滴下添加した。０．５時間撹拌後、塩化ピバロイル（３４ｇ、０．２８モル）を滴下添加した。この混合物を−７８℃で１時間撹拌した。次いで反応を飽和水性ＮＨ_４Ｃｌでクエンチし、この混合物をＥｔＯＡｃで抽出した。抽出物をＭｇＳＯ_４で乾燥させ、濃縮することによって、白色の固体として、（Ｓ）−５−ビフェニル−４−イルメチル−１−（２，２−ジメチルプロピオニル）ピロリジン−２−オンを得た（８５ｇ）。

[(S) -2-Biphenyl-4-yl-1- (2,2-dimethyl-4,6-dioxo- [1,3] dioxan-5-ylmethyl) ethyl] -carbamic acid t-butyl ester (143 g , 320 mmol) in anhydrous toluene (1 L) was heated to reflux overnight under nitrogen. The solvent was removed under reduced pressure to give (S) -2-biphenyl-4-ylmethyl-5-oxopyrrolidine-1-carboxylic acid t-butyl ester. This was used as is without further purification and added to a solution of 3N HCl in EtOAc (1.2 L). The resulting mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was recrystallized in EtOAc (300 mL) to give a first batch of deprotected compound (56 g). A second batch of deprotected compound was obtained by applying the mother liquor to a chromatography column (eluted with EtOAc and hexane, 1: 1 to 100% EtOAc) (8 g). To a suspension of the deprotected compound (64 g, 250 mmol) in anhydrous THF (500 mL), BuLi (100 mL, 2.5 M in hexane) was added dropwise at −78 ° C. After stirring for 0.5 hour, pivaloyl chloride (34 g, 0.28 mol) was added dropwise. The mixture was stirred at -78 ° C for 1 hour. The reaction was then quenched with saturated aqueous NH ₄ Cl and the mixture was extracted with EtOAc. The extract was dried over MgSO ₄ and concentrated to give (S) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) pyrrolidin-2-one as a white solid ( 85 g).

（Ｓ）−５−ビフェニル−４−イルメチル−１−（２，２−ジメチルプロピオニル）ピロリジン−２−オン（４０ｇ、１２０ｍｍｏｌ）を無水ＴＨＦ（４００ｍＬ）に溶解させ、窒素下、−７８℃で撹拌した。これに、１．５当量のナトリウムビス（トリメチルシリル）アミドの２．０Ｍ ＴＨＦ溶液を５分間にわたり滴下添加した。淡黄色の混合物を、窒素下、−７８℃で２０分間撹拌し、続いて、ＴＨＦ中の２００ｍＬ溶液としてオキサジリジン（５３ｇ、１８０ｍｍｏｌ）をゆっくりと滴下添加した。この混合物を０．５時間撹拌した。反応を飽和水性ＮＨ_４Ｃｌでクエンチし、この混合物をＥｔＯＡｃ（１Ｌ）で抽出した。抽出物を１Ｎ ＨＣｌ（１Ｌ）で洗浄し、ＭｇＳＯ_４で乾燥させ、５００ｍＬの容量まで濃縮した。沈殿した白色の固体を濾過し、濾液を濃縮することによって、シリカゲル（２００ｇ）の添加後、溶媒を除去した。事前にヘキサン中で詰めたシリカゲル（９００ｇ）のカラム（８×８０ｃｍ）に残渣を入れた。溶出を最初にＤＣＭ：ヘキサン（１：１）で行った。オキサジリジンおよびイミンが完全に収集されたら、カラムをＤＣＭで溶出することによって、黄色の油として、（３Ｒ，５Ｒ）−５−ビフェニル−４−イルメチル−１−（２，２−ジメチルプロピオニル）−３−ヒドロキシピロリジン−２−オンを得た（２１ｇ、純度９８％）。

(S) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) pyrrolidin-2-one (40 g, 120 mmol) was dissolved in anhydrous THF (400 mL) and stirred at −78 ° C. under nitrogen. did. To this, 1.5 equivalents of a 2.0 M THF solution of sodium bis (trimethylsilyl) amide was added dropwise over 5 minutes. The pale yellow mixture was stirred at −78 ° C. under nitrogen for 20 minutes, followed by the slow addition of oxaziridine (53 g, 180 mmol) as a 200 mL solution in THF. The mixture was stirred for 0.5 hours. The reaction was quenched with saturated aqueous NH ₄ Cl and the mixture was extracted with EtOAc (1 L). The extract was washed with 1N HCl (1 L), dried over MgSO ₄ and concentrated to a volume of 500 mL. The precipitated white solid was filtered and the filtrate was concentrated to remove the solvent after addition of silica gel (200 g). The residue was placed in a column (8 × 80 cm) of silica gel (900 g) previously packed in hexane. Elution was first performed with DCM: hexane (1: 1). Once the oxaziridine and imine have been collected, the column is eluted with DCM to give (3R, 5R) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) -3 as a yellow oil. -Hydroxypyrrolidin-2-one was obtained (21 g, purity 98%).

  (3R, 5R) -5-biphenyl-4-ylmethyl-1- (2,2-dimethylpropionyl) -3-hydroxypyrrolidin-2-one (56 g, 0.156 mol) was added to EtOH (700 mL) and 12N HCl ( 700 mL). The mixture was heated to 90-95 ° C. for 20 hours. The mixture was concentrated on a water bath at 80 ° C. under reduced pressure. EtOH (100 mL) was added to the residue and the resulting mixture was filtered to give a yellow solid. This solid was suspended in 3N HCl / EtOH (800 mL). The mixture was refluxed for 3 hours. The solution was concentrated to a smaller volume (approximately 200 mL volume) and ether (200 mL) was added. The resulting slightly yellow solid was filtered and dried under reduced pressure to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (43 g). .

Preparation 4
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester

１−ブタノール（４０ｍＬ、４００ｍｍｏｌ）を氷浴内で冷却し、４Ｎ ＨＣｌの濃度を達成するまで、塩化アセチルを滴下添加した。この混合物を室温に温めた。（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；２５０ｍｇ、７１０μｍｏｌ）を酸性化したブタノール（１５ｍＬ）に加え、この混合物に蓋をし、３時間８０℃に加熱した。生成した生成物を真空下で乾燥させることによって、白色／オレンジ色のフレーク状の固体ＨＣｌ塩として、表題化合物を得た（２２０ｍｇ）。

1-Butanol (40 mL, 400 mmol) was cooled in an ice bath and acetyl chloride was added dropwise until a concentration of 4N HCl was achieved. The mixture was warmed to room temperature. (2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 250 mg, 710 μmol) was added to acidified butanol (15 mL) and the mixture was capped. Heated to 80 ° C. for 3 hours. The resulting product was dried under vacuum to give the title compound as a white / orange flaky solid HCl salt (220 mg).

  Example 1

Ａ．（２Ｒ，４Ｒ）−４−［（５−アセチル−２Ｈ−ピラゾール−３−カルボニル）アミノ］−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；５００ｍｇ、１ｍｍｏｌ、１．０当量）、５−アセチル−２Ｈ−ピラゾール−３−カルボン酸（３３０．４ｍｇ、２．１ｍｍｏｌ、１．５当量）、およびＨＡＴＵ（８２０ｍｇ、２．１ｍｍｏｌ、１．５当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（７５０μＬ）を加え、この混合物を１時間撹拌した。この混合物を真空下で乾燥させ、逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して生成物を精製することによって、ＴＦＡ塩として表題化合物（３００ｍｇ、純度９８％）を得た。Ｃ_２５Ｈ_２７Ｎ_３Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４５０．２０；測定値４５０．２。

A. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (R ⁷ = -CH ₂ CH ₃ )
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 500 mg, 1 mmol, 1.0 eq), 5-acetyl-2H-pyrazole-3-carvone Acid (330.4 mg, 2.1 mmol, 1.5 eq) and HATU (820 mg, 2.1 mmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (750 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and purified as the TFA salt by purifying the product using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA over 70 minutes). A compound (300 mg, purity 98%) was obtained. C ₂₅ MS m / z for _{H 27 N 3 O 5 [M} + H] + Calculated: 450.20; found 450.2.

B. (2R, 4R) -4-[(5-Acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (R ⁷ = H)
A portion of the purified ethyl ester (Compound A) (200 mg) was dissolved in EtOH (about 10 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). The mixture was monitored for 1 hour until final deprotection was complete. The mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound as a TFA salt (160 mg; purity 100%). MS m / z for _{C 23 H 23 N 3 O 5} [M + H] + Calculated: 422.16; Found: 422.2.

C. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (R ⁷ =-(CH ₂ ) ₃ CH ₃₎
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (HCl salt; 500 mg, 1 mmol, 1.0 equiv), 3-acetyl-1H-pyrazole-5-carvone Acid (330.4 mg, 2.1 mmol, 1.5 eq) and HATU (820 mg, 2.1 mmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (750 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and the product was purified using reverse phase chromatography to give the title compound as a TFA salt (45 mg; purity 95%). MS m / z for _{C 27 H 31 N 3 O 5} [M + H] + Calculated: 478.23; found 478.4.

D. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid 2-methoxyethyl ester (R ⁷ =-(CH ₂ ) ₂ OCH ₃ )
A saturated HCl solution in 2-methoxyethanol was prepared by dropwise addition of acetyl chloride (about 400 μL) to 10 mL of absolute alcohol. To this solution was added (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (21.3 mg, 47 .4 μmol) was added and the resulting mixture was heated to 60 ° C. for 1-2 hours. This material was dried under vacuum. The product was then purified using reverse phase chromatography to give the title compound as a TFA salt (10 mg; 100% purity) MS m / z [M + H] ⁺ against C ₂₆ H ₂₉ N ₃ O ₆ . Calculated value: 480.21; measured value: 480.4.

E. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo- [1,3 ] dioxol-4-yl methyl ester ^(R 7 = _-CH 2 -5- methyl - [1,3] dioxol-2-one)
(2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (20 mg, 50 μmol) in dry DMF (2 mL). Dissolved. Cesium carbonate (50 mg, 0.2 mmol) was added and the resulting mixture was stirred at 0 ° C. for 1 hour. 4-Chloromethyl-5-methyl-1,3-dioxol-2-one (20 mg, 0.1 mmol) was added and the resulting mixture was stirred at room temperature overnight. EtOAc (20 mL) was added and the mixture was washed with saturated aqueous NaCl (100 mL) and then dried under vacuum. The material was purified using reverse phase chromatography to give the title compound as a TFA salt (5 mg, purity 100%). MS m / z for _{C 28 H 27 N 3 O 8} [M + H] + Calculated: 534.18; Found: 534.4.

F. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid 2-morpholin-4-yl-ethyl ester (R ^{_{7 = - (CH 2) 2}} - morpholine)
(2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (50 mg, 120 μmol, 1.1 eq) and HATU (42 mg, 110 μmol, 1.0 eq) was mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. 4-morpholine ethanol (73 mg, 560 μmol, 5.0 eq) was added followed by DIPEA. The resulting mixture was stirred for 1 hour and then the material was dried under vacuum. The product was then purified using reverse phase chromatography to give the title compound as a TFA salt (ca. 4 mg, purity 95%). For _{C 29 H 34 N 4 O 6} , MS m / z [M + H] + Calculated: 535.25; Found: 535.4.

G. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid 2-methanesulfonylethyl ester (R ⁷ =-( _{CH 2) 2 -SO 2 -CH 3} )
2- (Methylsulfonyl) ethanol (690 mg, 5.6 mmol) was warmed to 40 ° C. and 0.5 eq. Acetyl chloride was added with stirring for 5 minutes. (2R, 4R) -4-[(5-acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (50 mg, 110 μmol) was added and the reaction vessel was added. And then heated to 70 ° C. for 2 hours. The product was then purified using reverse phase chromatography to give the title compound as a TFA salt (approximately 28 mg, purity 95%). MS m / z for _{C 26 H 29 N 3 O 7} S [M + H] + Calculated: 528.17; Found: 528.4.

Preparation 5
Acetoxy (diethoxyphosphoryl) acetic acid ethyl ester

エチル２−オキソ酢酸（５０％）（７４ｇ、７２４．８ｍｍｏｌ、１．０当量）を、０℃で撹拌しながら、窒素下で、亜リン酸水素ジエチル（５０ｇ、３６２．１ｍｍｏｌ、１．０当量）のトルエン（１００ｍＬ）溶液に滴下添加した。０℃で撹拌しながら、Ｅｔ_３Ｎ（１１０ｇ、１．１モル、３．０当量）を滴下添加した。生成した溶液を室温で１時間撹拌した。この混合物に、無水酢酸（３７ｇ、３６２．４ｍｍｏｌ、１．０当量）を０℃で撹拌しながら滴下添加した。生成した溶液を一晩室温で撹拌した。２Ｎ ＨＣｌを用いて溶液のｐＨ値を６に調整した。生成した溶液をＤＣＭ（３×１５０ｍＬ）で抽出し、有機層を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮した。シリカゲルカラムに残渣を充填し、ＥｔＯＡｃ：ヘキサン（１：２〜１：５）を用いて、淡黄色の液体として表題化合物を得た（５２ｇ）。

Ethyl 2-oxoacetic acid (50%) (74 g, 724.8 mmol, 1.0 equiv) was stirred at 0 ° C. under nitrogen with diethyl hydrogen phosphite (50 g, 362.1 mmol, 1.0 equiv) ) In toluene (100 mL). While stirring at 0 ° C., Et ₃ N (110 g, 1.1 mol, 3.0 eq) was added dropwise. The resulting solution was stirred at room temperature for 1 hour. To this mixture, acetic anhydride (37 g, 362.4 mmol, 1.0 eq) was added dropwise with stirring at 0 ° C. The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 using 2N HCl. The resulting solution was extracted with DCM (3 × 150 mL) and the organic layers were combined, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was loaded onto a silica gel column and the title compound was obtained as a pale yellow liquid (52 g) using EtOAc: hexane (1: 2-1: 5).

Preparation 6
[(R) -2-Biphenyl-4-yl-1- (methoxymethylcarbamoyl) ethyl] carbamic acid t-butyl ester

ステップ１：Ｎ−ｔ−Ｂｏｃ−Ｄ−チロシン（８０．０ｇ、２８４．４ｍｍｏｌ、１．０当量）、Ｏ，Ｎ−ジメチル−ヒドロキシルアミン塩酸塩（３３．３ｇ、３４１．４ｍｍｏｌ、１．２当量）、１−エチル−３−（（３−ジメチルアミノ）−プロピル）カルボジイミド塩酸塩（８１．８ｇ、４２６．７ｍｍｏｌ、１．５当量）、ヒドロキシベンゾトリアゾール（５７．６ｇ、４２６．４ｍｍｏｌ、１．５当量）、およびＤＣＭ（乾燥）（８００ｍＬ）を、撹拌しながら窒素下で混合した。生成した混合物を０℃に冷却し、Ｅｔ_３Ｎ（４４．０ｇ、４３４．８ｍｍｏｌ、１．５３当量）を撹拌しながら４０分間にわたり滴下添加した。生成した溶液を室温で一晩撹拌し、次いでＮａＨＣＯ_３飽和水溶液（２×３００ｍＬ）で洗浄した。有機層を分離し、水層をＤＣＭ（２００ｍＬ）で再抽出した。有機相を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮することによって、黄色の固体として粗製の化合物１（１００ｇ）を得た。

Step 1: Nt-Boc-D-tyrosine (80.0 g, 284.4 mmol, 1.0 eq), O, N-dimethyl-hydroxylamine hydrochloride (33.3 g, 341.4 mmol, 1.2 eq) ), 1-ethyl-3-((3-dimethylamino) -propyl) carbodiimide hydrochloride (81.8 g, 426.7 mmol, 1.5 eq), hydroxybenzotriazole (57.6 g, 426.4 mmol, 1. 5 equivalents), and DCM (dry) (800 mL) were mixed under nitrogen with stirring. The resulting mixture was cooled to 0 ° C. and Et ₃ N (44.0 g, 434.8 mmol, 1.53 eq) was added dropwise over 40 minutes with stirring. The resulting solution was stirred overnight at room temperature and then washed with saturated aqueous NaHCO ₃ (2 × 300 mL). The organic layer was separated and the aqueous layer was re-extracted with DCM (200 mL). The organic phases were combined, dried over Na ₂ SO ₄ and concentrated in vacuo to give crude compound 1 (100 g) as a yellow solid.

ステップ２：化合物１（１００．０ｇ、粗製、３０８．３ｍｍｏｌ、１．０当量）、ピリジン（６１．０ｇ、７７１．２ｍｍｏｌ、２．５当量）、およびＤＣＭ（乾燥）（１０００ｍＬ）を、撹拌しながら窒素下で混合した。生成した混合物を−２０℃に冷却し、次いでトリフルオロメタンスルホン酸無水物（１０４．０ｇ、３６８．６ｍｍｏｌ、１．２当量）を、撹拌しながら−２０℃で３０分間にわたり滴下添加した。次いで生成した溶液を、−２０〜−１５℃で３０分間撹拌した。次いで、水（２５０ｍＬ）の添加により反応をクエンチした。生成した混合物を、０．５Ｎ ＮａＯＨ溶液（２×３００ｍＬ）および１５％クエン酸溶液（２×３００ｍＬ）で洗浄した。塩基性の水層をＤＣＭ（２００ｍＬ）で再抽出し、有機相を合わせ、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮した。残渣をシリカゲルカラムに充填し、ＥｔＯＡｃ：ヘキサン（０〜１：５）を用いて、薄黄色の油として化合物２（９７．７ｇ）を得た。

Step 2: Compound 1 (100.0 g, crude, 308.3 mmol, 1.0 equiv), pyridine (61.0 g, 771.2 mmol, 2.5 equiv), and DCM (dry) (1000 mL) were stirred. While mixing under nitrogen. The resulting mixture was cooled to −20 ° C. and then trifluoromethanesulfonic anhydride (104.0 g, 368.6 mmol, 1.2 eq) was added dropwise at −20 ° C. over 30 minutes with stirring. The resulting solution was then stirred at -20 to -15 ° C for 30 minutes. The reaction was then quenched by the addition of water (250 mL). The resulting mixture was washed with 0.5N NaOH solution (2 × 300 mL) and 15% citric acid solution (2 × 300 mL). The basic aqueous layer was re-extracted with DCM (200 mL) and the organic phases were combined, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was loaded onto a silica gel column and EtOAc: hexane (0 to 1: 5) was used to give compound 2 (97.7 g) as a pale yellow oil.

ステップ３：フェニルボロン酸（５３．０ｇ、４３４．７ｍｍｏｌ、２．０３当量）、炭酸カリウム（４５．０ｇ、３２５．６ｍｍｏｌ、１．５２当量）、テトラキス（トリフェニルホスフィン）パラジウム（０）（１２．５ｇ、１０．８ｍｍｏｌ、０．０５当量）、およびトルエン（蒸留）（８００ｍＬ）を、撹拌しながら窒素下で混合した。生成した懸濁液を脱気し、８０℃に加熱してから、化合物２（９７．７ｇ、２１４．１ｍｍｏｌ、１．０当量）のトルエン（２００ｍＬ）溶液を加えた。高粘度の懸濁液を、８０℃で一晩撹拌した。反応進行をＬＣＭＳでモニターし、これが不完全反応を指摘した。粗生成物／出発物質混合物をクロマトグラフィーで回収した後、さらなるフェニルボロン酸（２１．２ｇ）、炭酸カリウム（１８．０ｇ）、テトラキス（トリフェニルホスフィン）パラジウム（０）（５．０ｇ）を加え、生成した混合物をトルエン（蒸留）（７００ｍＬ）中に懸濁させた。生成した混合物を８０℃に加熱し、一晩撹拌した。完了時、水（３００ｍＬ）の添加によりこの反応をクエンチした。この混合物をＥｔＯＡｃ（２×３００ｍＬ）で抽出し、有機層を合わせた。有機相を飽和水性ＮａＣｌ（１×３００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、真空下で濃縮した。残渣をシリカゲルカラムに充填し、ＥｔＯＡｃ：ヘキサン（０〜１：３）を用いて、白色の固体として表題化合物を得た（５０．０ｇ）。

Step 3: Phenylboronic acid (53.0 g, 434.7 mmol, 2.03 eq), potassium carbonate (45.0 g, 325.6 mmol, 1.52 eq), tetrakis (triphenylphosphine) palladium (0) (12 0.5 g, 10.8 mmol, 0.05 eq), and toluene (distilled) (800 mL) were mixed under nitrogen with stirring. The resulting suspension was degassed and heated to 80 ° C. before adding a solution of compound 2 (97.7 g, 214.1 mmol, 1.0 equiv) in toluene (200 mL). The high viscosity suspension was stirred at 80 ° C. overnight. The reaction progress was monitored by LCMS, indicating an incomplete reaction. After the crude product / starting material mixture was recovered by chromatography, additional phenylboronic acid (21.2 g), potassium carbonate (18.0 g), tetrakis (triphenylphosphine) palladium (0) (5.0 g) were added. The resulting mixture was suspended in toluene (distilled) (700 mL). The resulting mixture was heated to 80 ° C. and stirred overnight. Upon completion, the reaction was quenched by the addition of water (300 mL). The mixture was extracted with EtOAc (2 × 300 mL) and the organic layers were combined. The organic phase was washed with saturated aqueous NaCl (1 × 300 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was loaded onto a silica gel column and the title compound was obtained as a white solid (50.0 g) using EtOAc: hexane (0 to 1: 3).

Preparation 7
((R) -2-Biphenyl-4-yl-1-formylethyl) carbamic acid t-butyl ester

［（Ｒ）−２−ビフェニル−４−イル−１−（メトキシメチルカルバモイル）エチル］カルバミン酸ｔ−ブチルエステル（７．５ｇ、１９．５ｍｍｏｌ、１．０当量）を、窒素下、ＴＨＦ（蒸留）（１００ｍＬ）と混合した。水素化リチウムアルミニウム（７５０ｍｇ、１９．８ｍｍｏｌ、１．０当量）を、いくつかのバッチで、生成した撹拌溶液に−５〜０℃で３０分間にわたり加えた。生成した溶液を、−５〜０℃で３０分間撹拌した。次いで、ＫＨＳＯ_４（６．６ｇ）の水（３５ｍＬ）溶液を添加することによって、この反応をクエンチした。生成した溶液を１Ｎ ＨＣｌ（７５ｍＬ）溶液と混合し、５分間撹拌した。ＥｔＯＡｃ（１００ｍＬ）を加え、生成した溶液をＥｔＯＡｃ（３×１００ｍＬ）で抽出し、有機層を合わせることによって、黄色の油として表題化合物（６．３ｇ）を得た。

[(R) -2-Biphenyl-4-yl-1- (methoxymethylcarbamoyl) ethyl] carbamic acid t-butyl ester (7.5 g, 19.5 mmol, 1.0 eq) was dissolved in THF (distilled) under nitrogen. ) (100 mL). Lithium aluminum hydride (750 mg, 19.8 mmol, 1.0 equiv) was added in several batches to the resulting stirred solution at −5 to 0 ° C. over 30 minutes. The resulting solution was stirred at −5 to 0 ° C. for 30 minutes. The reaction was then quenched by the addition of a solution of KHSO ₄ (6.6 g) in water (35 mL). The resulting solution was mixed with 1N HCl (75 mL) solution and stirred for 5 minutes. EtOAc (100 mL) was added and the resulting solution was extracted with EtOAc (3 × 100 mL) and the organic layers were combined to give the title compound (6.3 g) as a yellow oil.

Preparation 8
(R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester

ステップ１：アセトキシ（ジエトキシホスホリル）酢酸エチルエステル（１５．６ｇ、５５．３ｍｍｏｌ、１．２当量）のＴＨＦ（乾燥）（１５０ｍＬ）溶液を、窒素下、−７８℃に冷却した。ＬｉＨＭＤＳ（ＴＨＦ中１Ｍ）（５５．３ｍＬ、１．２当量）を、撹拌しながら−７８℃で滴下添加した。その温度で３０分間撹拌後、（（Ｒ）−２−ビフェニル−４−イル−１−ホルミルエチル）カルバミン酸ｔ−ブチルエステル（１５．０ｇ、粗製、１．０当量）のＴＨＦ（乾燥）（３０ｍＬ）溶液を１５分間にわたり滴下添加した。撹拌を−７８℃で１．５時間継続してから、この混合物を、水（２００ｍＬ）およびＥｔＯＡｃ（２００ｍＬ）の冷たい溶液に注ぎ入れた。有機層を繰り返し分離し、水層をＥｔＯＡｃ（２×１００ｍＬ）で再抽出した。合わせた有機層をＮａ_２ＳＯ_４で乾燥させ、濾過し、蒸発させ、残渣をフラッシュクロマトグラフィー（ＥｔＯＡｃ／ヘキサン＝０〜１：１０）で精製することによって、白色の固体として化合物１（１０．５ｇ）を得た。

Step 1: A solution of acetoxy (diethoxyphosphoryl) acetic acid ethyl ester (15.6 g, 55.3 mmol, 1.2 eq) in THF (dry) (150 mL) was cooled to −78 ° C. under nitrogen. LiHMDS (1M in THF) (55.3 mL, 1.2 eq) was added dropwise at −78 ° C. with stirring. After stirring at that temperature for 30 minutes, ((R) -2-biphenyl-4-yl-1-formylethyl) carbamic acid t-butyl ester (15.0 g, crude, 1.0 equivalent) in THF (dry) ( 30 mL) solution was added dropwise over 15 minutes. Stirring was continued at −78 ° C. for 1.5 hours before the mixture was poured into a cold solution of water (200 mL) and EtOAc (200 mL). The organic layer was repeatedly separated and the aqueous layer was re-extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated, and the residue was purified by flash chromatography (EtOAc / hexane = 0 to 1:10) to give compound 1 (10. 5 g) was obtained.

ステップ２：ＥｔＯＨ（無水）（１００ｍＬ）中の化合物１（１０．５ｇ、２３．２ｍｍｏｌ、１．０当量）の撹拌溶液を窒素下でパラジウム炭素（１．０ｇ）と混合した。この混合物を４回水素でパージし、次いで室温で２時間にわたり水素をバブリングした。パラジウム炭素を濾過して除き、濾液を真空下で濃縮することによって、薄黄色の油として、粗製の化合物２を得た（１０．０ｇ）。これをさらなる精製なしで使用した。

Step 2: A stirred solution of compound 1 (10.5 g, 23.2 mmol, 1.0 eq) in EtOH (anhydrous) (100 mL) was mixed with palladium on carbon (1.0 g) under nitrogen. The mixture was purged with hydrogen four times and then bubbled with hydrogen at room temperature for 2 hours. Palladium on carbon was filtered off and the filtrate was concentrated in vacuo to give crude compound 2 as a pale yellow oil (10.0 g). This was used without further purification.

ステップ３：ＥｔＯＨ（無水）（１００ｍＬ）中の化合物２（１０．０ｇ、２２．０ｍｍｏｌ、１．０当量）を炭酸カリウム（６．１ｇ、４４．１ｍｍｏｌ、２．０当量）と混合し、生成した溶液を室温で２時間撹拌した。固体を濾過して除き、濾液を真空下で濃縮した。残渣をシリカゲルカラムに充填し（ＥｔＯＡｃ／ヘキサン＝０〜１：５）、白色の固体として化合物３（６．０ｇ）を得た。

Step 3: Compound 2 (10.0 g, 22.0 mmol, 1.0 equiv) in EtOH (anhydrous) (100 mL) is mixed with potassium carbonate (6.1 g, 44.1 mmol, 2.0 equiv) to form The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off and the filtrate was concentrated under vacuum. The residue was loaded onto a silica gel column (EtOAc / hexane = 0 to 1: 5) to give compound 3 (6.0 g) as a white solid.

ステップ４：化合物３（６．０ｇ、１４．５ｍｍｏｌ、１．０当量）をＤＣＭ（乾燥）（１２０ｍＬ）に溶解させ、室温で５〜６時間にわたりＨＣｌをこの混合物中へバブリングした。固体の沈殿物が認められた。この混合物を半分の容量に濃縮し、次いで濾過した。固体を収集し、冷たいＥｔＯＡｃで洗浄し、減圧で乾燥させることによって、オフホワイト色の固体のＨＣｌ塩として表題化合物を得た（４．２ｇ）。ＬＣ−ＭＳ（ＥＳ、ｍ／ｚ）：３１４［Ｍ−ＨＣｌ＋Ｈ］^＋。
^１Ｈ ＮＭＲ （３００ ＭＨｚ， ＤＭＳＯ）： δ （ｐｐｍ） ＝８．０７ （ｓ， １．９Ｈ）， ７．９６ （ｓ， １．２Ｈ）， ７．６５−７．６９ （ｍ， ４．０Ｈ）， ７．４５−７．５ ０（ｍ， ２．０Ｈ）， ７．３３−７．３９ （ｍ， ３．０Ｈ）， ６．０５−６．０７ （ｍ， ０．６３Ｈ）， ５．８８−５．９０ （ｍ， ０．８８Ｈ）， ４．３２−４．３８ （ｍ， ０．８０Ｈ）， ４．１８−４．３１ （ｍ， ０．５１Ｈ）， ４．０５−４．１１ （ｍ， ２Ｈ）， ３．５０ （ｓ， １Ｈ）， ２．７５−３．０５ （ｍ， ２．８Ｈ）， １．８３−１．９４ （ｍ， １Ｈ）， １．７１−１．８２ （ｍ， １Ｈ）， １．１０−１．２０ （ｍ， ３．３Ｈ）。

Step 4: Compound 3 (6.0 g, 14.5 mmol, 1.0 equiv) was dissolved in DCM (dry) (120 mL) and HCl was bubbled into the mixture at room temperature for 5-6 hours. A solid precipitate was observed. The mixture was concentrated to half volume and then filtered. The solid was collected, washed with cold EtOAc and dried under reduced pressure to give the title compound as an off-white solid HCl salt (4.2 g). LC-MS (ES, m / z): 314 [M-HCl + H] ^< +>.
¹ H NMR (300 MHz, DMSO): δ (ppm) = 8.07 (s, 1.9H), 7.96 (s, 1.2H), 7.65-7.69 (m, 4.0H) ), 7.45-7.50 (m, 2.0H), 7.33-7.39 (m, 3.0H), 6.05-6.07 (m, 0.63H), 5. 88-5.90 (m, 0.88H), 4.32-4.38 (m, 0.80H), 4.18-4.31 (m, 0.51H), 4.05-4.11 (M, 2H), 3.50 (s, 1H), 2.75-3.05 (m, 2.8H), 1.83-1.94 (m, 1H), 1.71-1.82 (M, 1H), 1.10-1.20 (m, 3.3H).

  (Example 2)

Ａ．５−（（１Ｒ，３Ｓ）−１−ビフェニル−４−イルメチル−３−エトキシカルボニル−３−ヒドロキシプロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸（Ｒ^７＝−ＣＨ_２ＣＨ_３）
Ｂ．５−（（１Ｒ，３Ｒ）−１−ビフェニル−４−イルメチル−３−エトキシカルボニル−３−ヒドロキシプロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸（Ｒ^７＝−ＣＨ_２ＣＨ_３）
Ｃ．５−（（１Ｒ，３Ｓ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸（Ｒ^７＝Ｈ）
Ｄ．５−（（１Ｒ，３Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸（Ｄ；Ｒ^７＝Ｈ）
（Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（５００ｍｇ、１．６ｍｍｏｌ、１．０当量）、３，５−ピラゾールジカルボン酸（２５０ｍｇ、１．６ｍｍｏｌ、１．６当量）、およびＨＡＴＵ（６１０ｍｇ、１．６ｍｍｏｌ、１．０当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（１ｍＬ）を加え、この混合物を１時間撹拌した。この混合物を真空下で乾燥させ、逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用してこの生成物を精製することによって、ＴＦＡ塩として、５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−エトキシカルボニル−３−ヒドロキシプロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸を得た。

A. 5-((1R, 3S) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid (R ⁷ = —CH ₂ CH ₃ )
B. 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid (R ⁷ = —CH ₂ CH ₃ )
C. 5-((1R, 3S) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid (R ⁷ = H)
D. 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid (D; R ⁷ = H)
(R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (500 mg, 1.6 mmol, 1.0 eq), 3,5-pyrazole dicarboxylic acid (250 mg, 1.6 mmol, 1.6 equiv), and HATU (610 mg, 1.6 mmol, 1.0 equiv) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (1 mL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and purified as a TFA salt by purifying the product using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA over 70 minutes). , 5-((R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxypropylcarbamoyl) -2H-pyrazole-3-carboxylic acid was obtained.

This material was separated by preparative HPLC, purified using reverse phase chromatography, and dried under vacuum to give compounds A and B as TFA salts. Compounds A and B were each dissolved in EtOH (about 100 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). Each mixture was monitored for 1 hour until final deprotection was complete. Each mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the compound C (52 mg; 100% purity; MS m / z [M + H] ⁺ C ₂₂ H ₂₁ N ₃ O ₆ as TFA salt ⁺ calculated: 424.14; found 424.2) and compound D (65 mg; 100% purity; MS m / z [M + H] for C ₂₂ H ₂₁ N ₃ O ₆ ⁺ calculated: 424.14; found: 424.2. )

E. 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-butoxycarbonyl-3-hydroxy-propylcarbamoyl) -1H-pyrazole-3-carboxylic acid (R ⁷ = — (CH ₂ ) ₃ CH ₃ )
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid butyl ester (HCl salt; 108 mg, 286 μmmol, 1.0 eq), 3,5-pyrazole dicarboxylic acid (66.9 mg 429 μmol, 1.5 eq), and HATU (160 mg, 430 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (150 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and the product was purified using reverse phase chromatography to give the title compound as a TFA salt (60 mg; purity 98%). MS m / z for _{C 26 H 29 N 3 O 6} [M + H] + Calculated: 480.21; Found 480.4).

  (Example 3)

Ａ．（２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（２−メトキシエチル）メチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
Ｂ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（２−メトキシエチル）メチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
Ｃ．（２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（２−メトキシエチル）メチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸（Ｒ^７＝Ｈ）
Ｄ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（２−メトキシエチル）メチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸（Ｒ^７＝Ｈ）
（Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（９００ｍｇ、３．０ｍｍｏｌ、１．０当量）、３，５−ピラゾールジカルボン酸（４４８ｍｇ、２．９ｍｍｏｌ、１．０当量）、Ｎ−（２−メトキシエチル）メチルアミン（２５６ｍｇ、２．９ｍｍｏｌ、１．０当量）、およびＨＡＴＵ（１０９０ｍｇ、２．９ｍｍｏｌ、１．０当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（１ｍＬ）を加え、この混合物を１時間撹拌した。この混合物を真空下で乾燥させ、逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して生成物を精製することによって、ＴＦＡ塩として、（Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（２−メトキシエチル）メチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）−ペンタン酸エチルエステル（２５ｍｇ）を得た。

A. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) pentanoic acid ethyl ester ( R ⁷ = _-CH 2 _CH 3)
B. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) pentanoic acid ethyl ester ( R ⁷ = _-CH 2 _CH 3)
C. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) pentanoic acid (R ⁷ = H)
D. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) pentanoic acid (R ⁷ = H)
(R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (900 mg, 3.0 mmol, 1.0 eq), 3,5-pyrazole dicarboxylic acid (448 mg, 2.9 mmol, 1.0 equiv), N- (2-methoxyethyl) methylamine (256 mg, 2.9 mmol, 1.0 equiv), and HATU (1090 mg, 2.9 mmol, 1.0 equiv) in DMF (5 mL). Mix and stir the resulting mixture for 2 minutes. DIPEA (1 mL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum and purified as a TFA salt by purifying the product using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA over 70 min). (R) -5-biphenyl-4-yl-2-hydroxy-4-({5-[(2-methoxyethyl) methylcarbamoyl] -2H-pyrazole-3-carbonyl} amino) -pentanoic acid ethyl ester (25 mg )

This material was separated by preparative HPLC, purified using reverse phase chromatography, and dried under vacuum to give compounds A and B as TFA salts. Compounds A and B were each dissolved in EtOH (about 10 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). Each mixture was monitored for 1 hour until final deprotection was complete. Each mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the compound C (20.6 mg; 100% purity; MS m / z [M + H] ⁺ calculated for C ₂₆ H ₃₀ N ₄ O ₆ as the TFA salt ⁺ calculated value. : 495.22; Found: 495.22) and D (8.3 mg; purity _100%; MS m / z for _{C 26 H 30 N 4 O 6} [M + H] + calculated: 495.22; Found: 495.22) was obtained.

  Example 4

Ａ．（２Ｒ，４Ｒ）−４−｛［５−（アゼチジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；１００ｍｇ、２８６μｍｏｌ、１．０当量）、３，５−ピラゾールジカルボン酸（６６．９ｍｇ、４２９μｍｏｌ、１．５当量）、およびＨＡＴＵ（１６０ｍｇ、４３０μｍｏｌ、１．５当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（１５０μＬ）を加え、この混合物を１時間撹拌した。アゼチジン塩酸塩（４０．０ｍｇ、４２９μｍｏｌ、１．５当量）を、別の当量のＨＡＴＵと共に加え、この混合物を短い間撹拌した。さらなるＤＩＰＥＡ（２．０当量）を加え、この混合物を撹拌した。この混合物を真空下で乾燥させ、次いで、逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して精製することによって、ＴＦＡ塩として、表題化合物を得た（２０ｍｇ；純度９５％）。Ｃ_２７Ｈ_３０Ｎ_４Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４９１．２２；計算値：４９１．４。

A. (2R, 4R) -4-{[5- (azetidine-1-carbonyl) -2H-pyrazole-3-carbonyl] amino} -5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (R ⁷ = -CH ₂ CH ₃₎
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 100 mg, 286 μmol, 1.0 eq), 3,5-pyrazole dicarboxylic acid (66.9 mg 429 μmol, 1.5 eq), and HATU (160 mg, 430 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (150 μL) was added and the mixture was stirred for 1 hour. Azetidine hydrochloride (40.0 mg, 429 μmol, 1.5 eq) was added along with another equivalent of HATU and the mixture was stirred briefly. Additional DIPEA (2.0 eq) was added and the mixture was stirred. The mixture was dried under vacuum and then purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA, over 70 min) as the TFA salt. The compound was obtained (20 mg; purity 95%). MS m / z for _{C 27 H 30 N 4 O 5} [M + H] + calculated: 491.22; Calculated: 491.4.

B. (2R, 4R) -4-{[5- (azetidine-1-carbonyl) -2H-pyrazole-3-carbonyl] amino} -5-biphenyl-4-yl-2-hydroxy-pentanoic acid (R ⁷ = H )
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 50 mg, 0.1 mmol, 1.0 equivalent), 3,5-pyrazole dicarboxylic acid monohydrate The Japanese (29.9 mg, 173 μmol, 1.2 eq), and HATU (82 mg, 210 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (75 μL) was added and the mixture was stirred for 1 hour. Azetidine hydrochloride (20.0 mg, 214 μmol, 1.5 eq) was added along with another equivalent of HATU and the mixture was stirred briefly. The mixture was dried under vacuum to give the crude ester. The crude ester was dissolved in EtOH (about 10 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). The mixture was monitored for 1 hour until final deprotection was complete. The mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound as a TFA salt (17 mg; purity 95%). C ₂₅ H ₂₆ N ₄ O ₅ with respect to MS m / z [M + H ] + Calculated: 463.19; Found: 463.4.

  (Example 5)

Ａ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（ピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；８５ｍｇ、２４０μｍｏｌ、１．０当量）、３，５−ピラゾールジカルボン酸一水和物（４０ｍｇ、０．２ｍｍｏｌ、１．０当量）、およびＨＡＴＵ（９０ｍｇ、０．２ｍｍｏｌ、１．０当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（１５０μＬ）を加え、この混合物を１時間撹拌した。別の当量のＨＡＴＵを加え、続いてピロリジン（２０．３μＬ、２４３μｍｏｌ、１．０当量）（ＴＨＦ中１Ｎ）および別の当量のＤＩＰＥＡを加えた。反応完了時に、この混合物を真空下で乾燥させ、次いで逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して精製することによって、ＴＦＡ塩として表題化合物を得た（６５ｍｇ；純度９８％）。Ｃ_２８Ｈ_３２Ｎ_４Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：５０５．２４；測定値：５０５．４。

A. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (pyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] amino} pentanoic acid ethyl ester (R ⁷ = -CH ₂ CH ₃₎
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 85 mg, 240 μmol, 1.0 eq), 3,5-pyrazole dicarboxylic acid monohydrate (40 mg, 0.2 mmol, 1.0 equiv), and HATU (90 mg, 0.2 mmol, 1.0 equiv) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (150 μL) was added and the mixture was stirred for 1 hour. Another equivalent of HATU was added, followed by pyrrolidine (20.3 μL, 243 μmol, 1.0 equivalent) (1N in THF) and another equivalent of DIPEA. Upon completion of the reaction, the mixture was dried under vacuum and then purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA, over 70 minutes) to give a TFA salt. As the title compound (65 mg; purity 98%). MS m / z for _{C 28 H 32 N 4 O 5} [M + H] + Calculated: 505.24; Found: 505.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (pyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} pentanoic acid (R ⁷ = H )
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 50 mg, 0.1 mmol, 1.0 equivalent), 3,5-pyrazole dicarboxylic acid monohydrate The Japanese (20.0 mg, 0.1 mmol, 1.0 equiv) and HATU (50 mg, 0.1 mmol, 1.0 equiv) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA (75 μL) was added and the mixture was stirred for 1 hour. Another equivalent of HATU was added, followed by pyrrolidine (20.0 mg, 280 μmol, 2.0 equivalents) and another equivalent of DIPEA. The mixture was dried under vacuum to give the crude ester. The crude ester was dissolved in EtOH (about 10 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). The mixture was monitored for 1 hour until final deprotection was complete. The mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound as a TFA salt (25 mg; purity 95%). MS m / z for _{C 26 H 28 N 4 O 5} [M + H] + Calculated: 477.21; Found: 477.0.

  (Example 6)

Ａ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（２−ヒドロキシピリミジン−５−カルボニル）アミノ］ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
Ｂ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（２−ヒドロキシピリミジン−５−カルボニル）アミノ］ペンタン酸（Ｒ^７＝Ｈ）
（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；２００ｍｇ、５７２μｍｏｌ、１．０当量）および２−ヒドロキシピリミジン−５−カルボン酸（８８．１ｍｇ、６２９μｍｏｌ）をＤＭＦ（５．０ｍＬ）中に懸濁させた。ＨＡＴＵ（２３９ｍｇ、６２９μｍｏｌ）を加え、続いてＤＩＰＥＡ（２９９μＬ）を加え、反応が完了するまで（約２時間）、生成した混合物を室温で撹拌した。この混合物を等しく２つに分割し、両方の溶液を濃縮した。一方を分取ＨＰＬＣ（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ）で精製することによって、ＴＦＡ塩として、化合物Ａを得た（５９．２ｍｇ）。Ｃ_２４Ｈ_２５Ｎ_３Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４３６．１８；測定値４３６．４。残りをＴＨＦ（２．０ｍＬ）に溶解させた。水（２．０ｍＬ）中のＬｉＯＨ一水和物（１２０ｍｇ、２．９ｍｍｏｌ）を加え、この混合物を、室温で約１時間撹拌した。ＡｃＯＨの添加により反応をクエンチし、溶液を濃縮した。分取ＨＰＬＣ（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ）により粗生成物を精製することによって、ＴＦＡ塩として、化合物Ｂを得た（２７．８ｍｇ）。Ｃ_２２Ｈ_２１Ｎ_３Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４０８．１５；測定値４０８．４。

A. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5-carbonyl) amino] pentanoic acid ethyl ester (R ⁷ = —CH ₂ CH ₃ )
B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5-carbonyl) amino] pentanoic acid (R ⁷ = H)
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 eq) and 2-hydroxypyrimidine-5-carboxylic acid (88 .1 mg, 629 μmol) was suspended in DMF (5.0 mL). HATU (239 mg, 629 μmol) was added followed by DIPEA (299 μL) and the resulting mixture was stirred at room temperature until the reaction was complete (about 2 hours). This mixture was divided equally into two and both solutions were concentrated. One was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give Compound A as a TFA salt (59.2 mg). C ₂₄ H ₂₅ N ₃ O ₅ with respect to MS m / z [M + H ] + Calculated: 436.18; found 436.4. The rest was dissolved in THF (2.0 mL). LiOH monohydrate (120 mg, 2.9 mmol) in water (2.0 mL) was added and the mixture was stirred at room temperature for about 1 hour. The reaction was quenched by the addition of AcOH and the solution was concentrated. The crude product was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give Compound B as a TFA salt (27.8 mg). MS m / z for _{C 22 H 21 N 3 O 5} [M + H] + Calculated: 408.15; found 408.4.

  (Example 7)

Ａ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３−ヒドロキシイソオキサゾール−５−カルボニル）アミノ］ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
３−ヒドロキシイソオキサゾール−５−カルボン酸（８１．２ｍｇ、６２９μｍｏｌ、１．１当量）をＤＭＦ（５．０ｍＬ）に溶解させた。ＤＩＰＥＡ（２９９μＬ）およびＨＯＡｔ（８５．６ｍｇ、６２９μｍｏｌ、１．１当量）を加え、続いてＥＤＣＩ（１１１μＬ、１．１当量）を加えた。この溶液を５分間撹拌した。次いで、（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；２００ｍｇ、５７２μｍｏｌ、１．０当量）を加え、生成した混合物を室温で一晩撹拌した。この混合物を濃縮し、分取ＨＰＬＣ（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ）で粗生成物を精製することによって、ＴＦＡ塩として表題化合物を得た（５０．８ｍｇ、９８％純度）。Ｃ_２３Ｈ_２４Ｎ_２Ｏ_６に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４２５．１６；測定値：４２５．４。

A. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl) amino] pentanoic acid ethyl ester (R ⁷ = —CH ₂ CH ₃ )
3-hydroxyisoxazole-5-carboxylic acid (81.2 mg, 629 μmol, 1.1 eq) was dissolved in DMF (5.0 mL). DIPEA (299 μL) and HOAt (85.6 mg, 629 μmol, 1.1 eq) were added followed by EDCI (111 μL, 1.1 eq). The solution was stirred for 5 minutes. Then (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 equiv) was added and the resulting mixture was stirred at room temperature. Stir overnight. The mixture was concentrated and the crude product was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give the title compound as a TFA salt (50.8 mg, 98% purity). MS m / z for _{C 23 H 24 N 2 O 6} [M + H] + Calculated: 425.16; Found: 425.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl) amino] pentanoic acid (R ⁷ = H)
(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 200 mg, 572 μmol, 1.0 equiv) and 3-hydroxyisoxazole-5-carboxylic acid ( 81.2 mg, 629 μmol) was suspended in DMF (5.0 mL). HATU (239 mg, 629 μmol) was added followed by DIPEA (299 μL) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the crude compound was used without purification. The crude product was dissolved in THF (3.0 mL). LiOH monohydrate (240 mg, 5.7 mmol) was added in water (3.0 mL) and the mixture was stirred at room temperature for about 1 hour. The mixture was concentrated and the crude product was purified by preparative HPLC (10-70% MeCN / H ₂ O) to give the title compound as a TFA salt (36.6 mg, 97% purity). MS m / z for _{C 21 H 20 N 2 O 6} [M + H] + Calculated: 397.13; Found: 397.2.

C. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(3-hydroxyisoxazole-5-carbonyl) amino] pentanoic acid 5-methyl-2-oxo- [1,3] dioxole 4-ylmethyl ester ^(R 7 = _-CH 2 -5- methyl - [1,3] dioxol-2-one)
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxy-pentanoic acid ethyl ester; hydrochloride (1.6 g, 4.6 mmol, 1.0 eq) dissolved in DCM (100 mL) And cooled to 0 ° C. Di-t-butyl dicarbonate (1.2 g, 5.4 mmol, 1.2 eq) was added as a solid followed by DIPEA (1.6 mL, 9.1 mmol). The resulting mixture was stirred overnight at room temperature. The product was purified by flash chromatography (0-75% EtOAc / hexane), then dissolved in EtOH and the solution was made basic by adding a sufficient equivalent of 10N NaOH (pH = 14). The reaction was monitored until deprotection was complete (about 1 hour). EtOAc (200 mL) was added and the mixture was washed with 1N HCl (100 mL) followed by saturated aqueous NaCl (100 mL). The organic layer was retained and dried over anhydrous MgSO ₄ for 10 minutes, then filtered and exhaust dried to give (2R, 4R) -5-biphenyl-4-yl-4-t-butoxycarbonylamino-2- Hydroxypentanoic acid was obtained (1.2 g).

(2R, 4R) -5-biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid (500 mg, 1.0 mmol, 1.0 equiv) was dissolved in dry DMF (10.0 mL). It was. The solution was cooled to 0 ° C. and dicesium carbonate (465 mg, 1.4 mmol, 1.1 eq) was added. The mixture was stirred for 30 minutes and 4-chloromethyl-5-methyl-1,3-dioxol-2-one (212 mg, 1.4 mmol, 1.1 eq) was added. The resulting mixture was stirred for an additional hour at 0 ° C. and then allowed to warm to room temperature with stirring. The mixture was further stirred overnight. EtOAc (20 mL) was added followed by washing with saturated aqueous NaCl (100 mL). The product is dried under vacuum and purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA, over 70 minutes) to give (2R, 4R) -5. -Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxypentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester was obtained. This material was dissolved in 4N HCl in dioxane and stirred at room temperature for 2 hours. The material is dried under vacuum and then azeotroped with toluene to give (2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo- [ 1,3] dioxol-4-ylmethyl ester was obtained. This was used in the next step without further purification.

(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester (100 mg, 0.3 mmol, 1.0 eq) and 3-hydroxyisoxazole-5-carboxylic acid (50.5 mg, 391 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was stirred for 2 min. DIPEA was added and the resulting mixture was stirred for 1 hour. The material was dried under vacuum and then purified using reverse phase chromatography to give the title compound (40 mg, 98% purity). MS m / z for _{C 26 H 24 N 2 O 9} [M + H] + Calculated: 509.15; Found: 509.4.

  (Example 8)

Ａ．（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（１−ヒドロキシ−１−メチルエチル）−１Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸エチルエステル（Ｒ^７＝−ＣＨ_２ＣＨ_３）
（２Ｒ，４Ｒ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸エチルエステル（ＨＣｌ塩；１００ｍｇ、０．３ｍｍｏｌ、１．０当量）、５−（１−ヒドロキシ−１−メチルエチル）−１Ｈ−ピラゾール−３−カルボン酸（７３ｍｇ、４２９μｍｍｏｌ、１．５当量）、およびＨＡＴＵ（１６０ｍｇ、４３０μｍｏｌ、１．５当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ＤＩＰＥＡ（１４９μＬ）を加え、この混合物を１時間撹拌した。反応完了時に、この混合物を真空下で乾燥させ、次いで逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して精製することによって、ＴＦＡ塩として、表題化合物を得た（５０ｍｇ）。Ｃ_２６Ｈ_３１Ｎ_３Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４６６．２３；測定値：４６６．４。

A. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy-1-methylethyl) -1H-pyrazole-3-carbonyl] amino} pentanoic acid ethyl ester ( R ⁷ = _-CH 2 _CH 3)
(2R, 4R) -4-amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 100 mg, 0.3 mmol, 1.0 equiv), 5- (1-hydroxy-1- Methylethyl) -1H-pyrazole-3-carboxylic acid (73 mg, 429 μmmol, 1.5 eq) and HATU (160 mg, 430 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was mixed with 2 Stir for minutes. DIPEA (149 μL) was added and the mixture was stirred for 1 hour. Upon completion of the reaction, the mixture was dried under vacuum and then purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA, over 70 minutes) to give a TFA salt. To give the title compound (50 mg). MS m / z for _{C 26 H 31 N 3 O 5} [M + H] + Calculated: 466.23; Found: 466.4.

B. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy-1-methylethyl) -1H-pyrazole-3-carbonyl] amino} pentanoic acid (R ⁷ = H)
(2R, 4R) -4-Amino-5-biphenyl-4-yl-2-hydroxypentanoic acid ethyl ester (HCl salt; 60 mg, 0.2 mmol, 1.0 eq), 5- (1-hydroxy-1- Methylethyl) -1H-pyrazole-3-carboxylic acid (43.8 mg, 257 μmol, 150 eq) and HATU (98 mg, 260 μmol, 1.5 eq) were mixed in DMF (5 mL) and the resulting mixture was mixed with 2 Stir for minutes. DIPEA (89.6 μL) was added and the mixture was stirred for 1 hour. The mixture was dried under vacuum to give the crude ester. The crude ester was dissolved in EtOH (about 10 mL) and the solution was made basic by adding 10 N NaOH (about 200 μL). The mixture was monitored for 1 hour until final deprotection was complete. The mixture was acidified with an equal volume (about 200 μL) of AcOH and dried under vacuum. The product was purified using reverse phase chromatography to give the title compound as a TFA salt (30 mg). C ₂₄ H ₂₇ N ₃ against _{O 5 MS m / z [M} + H] + Calculated: 438.20; Found: 438.4.

Example 9
2-hydroxypyrimidine-5-carboxylic acid ((1R, 3R) -1-biphenyl-4-ylmethyl-3-carbamoyl-3-hydroxypropyl) amide

（２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（２−ヒドロキシピリミジン−５−カルボニル）アミノ］ペンタン酸（１４．５ｍｇ、３５．６μｍｏｌ、１．０当量）およびＨＡＴＵ（１３．５ｍｇ、３５．６μｍｏｌ、１．０当量）をＤＭＦ（５ｍＬ）中で混合し、生成した混合物を２分間撹拌した。ジオキサン中０．５Ｍのアンモニアを加え、続いてＤＩＰＥＡ（１２．４μＬ）を加えた。生成した混合物を１時間撹拌し、次いで真空下で乾燥させた。逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ／Ｈ_２Ｏ；０．０５％ＴＦＡ、７０分間にわたって）を使用して、生成物を精製することによって、表題化合物を得た（２ｍｇ）。Ｃ_２２Ｈ_２２Ｎ_４Ｏ_４に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４０７．１６；測定値：４０７．４。

(2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(2-hydroxypyrimidine-5-carbonyl) amino] pentanoic acid (14.5 mg, 35.6 μmol, 1.0 eq) and HATU (13.5 mg, 35.6 μmol, 1.0 equiv) was mixed in DMF (5 mL) and the resulting mixture was stirred for 2 minutes. 0.5M ammonia in dioxane was added followed by DIPEA (12.4 μL). The resulting mixture was stirred for 1 hour and then dried under vacuum. The product was purified using reverse phase chromatography (10-70% MeCN / H ₂ O; 0.05% TFA, over 70 minutes) to give the title compound (2 mg). MS m / z for _{C 22 H 22 N 4 O 4} [M + H] + Calculated: 407.16; Found: 407.4.

  Following the procedures described in the examples herein, the compounds of Examples 10-15 having the following formulas were also prepared using the appropriate starting materials and reagents instead.

（実施例１０）
これらは、親化合物として、またはＴＦＡ塩として調製した。

(Example 10)
These were prepared as parent compounds or as TFA salts.

１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾール−４−カルボニル）アミノ］ペンタン酸エチルエステル（ＴＦＡ塩）
２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾール−４−カルボニル）アミノ］ペンタン酸（ＴＦＡ塩）

1. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) amino] pentanoic acid ethyl ester (TFA salt)
2. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) amino] pentanoic acid (TFA salt)

３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸
４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル（ＴＦＡ塩）

3. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester ( TFA salt)

５． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］ペンタン酸エチルエステル（ＴＦＡ塩）
６． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］ペンタン酸（ＴＦＡ塩）
７． （Ｒ）−５−ビフェニル−４−イル−４−｛［１−（４−クロロフェニル）−５−メチル−１Ｈ−［１，２，４］トリアゾール−３−カルボニル］−アミノ｝−２−ヒドロキシペンタン酸（ＴＦＡ塩）
８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ヒドロキシ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］−ペンタン酸エチルエステル（ＴＦＡ塩）
９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ヒドロキシ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］−ペンタン酸（ＴＦＡ塩）

5). (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid ethyl ester (TFA salt)
6). (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid (TFA salt)
7). (R) -5-biphenyl-4-yl-4-{[1- (4-chlorophenyl) -5-methyl-1H- [1,2,4] triazole-3-carbonyl] -amino} -2-hydroxy Pentanoic acid (TFA salt)
8). (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxy-1H- [1,2,4] triazole-3-carbonyl) amino] -pentanoic acid ethyl ester (TFA salt)
9. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-hydroxy-1H- [1,2,4] triazole-3-carbonyl) amino] -pentanoic acid (TFA salt)

１０． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−２−イル−４Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］ペンタン酸（ＴＦＡ塩）

10. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-4H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid (TFA salt) )

１１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−メチル−２Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］ペンタン酸（ＴＦＡ塩）
１２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−クロロ−２Ｈ−［１，２，４］トリアゾール−３−カルボニル）アミノ］−２−ヒドロキシペンタン酸。

11. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-methyl-2H- [1,2,4] triazole-3-carbonyl) amino] pentanoic acid (TFA salt)
12 (2R, 4R) -5-Biphenyl-4-yl-4-[(5-chloro-2H- [1,2,4] triazole-3-carbonyl) amino] -2-hydroxypentanoic acid.

(Example 11)
These were all prepared as TFA salts.

１． ３−［５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−ベンゾトリアゾール−１−イルメチル］−安息香酸
２． ４−［５−（（１Ｒ，３Ｓ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−ベンゾトリアゾール−１−イルメチル］−安息香酸
３． （Ｒ）−４−［（１Ｈ−ベンゾトリアゾール−５−カルボニル）アミノ］−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸
４． （Ｒ）−５−ビフェニル−４−イル−４−［（７−フルオロ−１Ｈ−ベンゾトリアゾール−５−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸
５． （Ｒ）−５−ビフェニル−４−イル−４−［（７−クロロ−１Ｈ−ベンゾトリアゾール−５−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸エチルエステル

1. 3- [5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -benzotriazol-1-ylmethyl] -benzoic acid 4- [5-((1R, 3S) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -benzotriazol-1-ylmethyl] -benzoic acid (R) -4-[(1H-benzotriazole-5-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxypentanoic acid (R) -5-biphenyl-4-yl-4-[(7-fluoro-1H-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid (R) -5-Biphenyl-4-yl-4-[(7-chloro-1H-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid ethyl ester

６． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（７−メチル−３Ｈ−ベンゾトリアゾール−５−カルボニル）アミノ］ペンタン酸

6). (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(7-methyl-3H-benzotriazole-5-carbonyl) amino] pentanoic acid

７． （Ｒ）−５−ビフェニル−４−イル−４−［（４−クロロ−１Ｈ−ベンゾトリアゾール−５−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸

7). (R) -5-biphenyl-4-yl-4-[(4-chloro-1H-benzotriazole-5-carbonyl) amino] -2-hydroxy-pentanoic acid

８． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（２−メチル−ベンゾオキサゾール−６−カルボニル）−アミノ］−ペンタン酸

8). (R) -5-biphenyl-4-yl-2-hydroxy-4-[(2-methyl-benzoxazole-6-carbonyl) -amino] -pentanoic acid

９． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−イミダゾ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸

9. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(3H-imidazo [4,5-b] pyridine-6-carbonyl) -amino] -pentanoic acid

１０． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸エチルエステル
１１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸

10. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -ethyl pentanoate Ester 11. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -pentanoic acid

１２． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸エチルエステル
１３． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸
１４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸エチルエステル
１５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾロ［４，５−ｂ］ピリジン−６−カルボニル）−アミノ］−ペンタン酸。

12 (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -pentane Acid ethyl ester13. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -pentane Acid 14. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -pentane Acid ethyl ester15. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(3H- [1,2,3] triazolo [4,5-b] pyridine-6-carbonyl) -amino] -pentane acid.

(Example 12)
These were prepared as parent compounds or as TFA salts.

１． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）フラン−２−カルボン酸（ＴＦＡ塩）

1. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) furan-2-carboxylic acid (TFA salt)

２． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）チオフェン−２−カルボン酸

2. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) thiophene-2-carboxylic acid

３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３−メトキシイソオキサゾール−５−カルボニル）アミノ］−ペンタン酸
４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（４−クロロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［３−（２−メトキシ−ベンゾイルアミノ）−イソオキサゾール−５−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（２−クロロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（３−シクロヘキシル−イソオキサゾール−５−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（３−フルオロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（２−フルオロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
１０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［３−（１−メチル−１Ｈ−ピラゾール−４−イル）−イソオキサゾール−５−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
１１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（２，５−ジクロロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
１２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（３，４−ジクロロフェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
１３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［３−（２−メトキシ−フェニル）−イソオキサゾール−５−カルボニル］−アミノ｝−ペンタン酸
１４． ５−（（１Ｒ，３Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−イソオキサゾール−３−カルボン酸

3. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(3-methoxyisoxazole-5-carbonyl) amino] -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (4-chlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)
5). (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[3- (2-methoxy-benzoylamino) -isoxazole-5-carbonyl] -amino} -pentanoic acid (TFA salt)
6). (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2-chlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)
7). (2R, 4R) -5-Biphenyl-4-yl-4-[(3-cyclohexyl-isoxazole-5-carbonyl) -amino] -2-hydroxy-pentanoic acid (TFA salt)
8). (2R, 4R) -5-biphenyl-4-yl-4-{[3- (3-fluorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-biphenyl-4-yl-4-{[3- (2-fluorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[3- (1-methyl-1H-pyrazol-4-yl) -isoxazole-5-carbonyl] -amino} -pentane Acid (TFA salt)
11. (2R, 4R) -5-biphenyl-4-yl-4-{[3- (2,5-dichlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-biphenyl-4-yl-4-{[3- (3,4-dichlorophenyl) -isoxazole-5-carbonyl] -amino} -2-hydroxy-pentanoic acid; (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[3- (2-methoxy-phenyl) -isoxazole-5-carbonyl] -amino} -pentanoic acid; 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -isoxazole-3-carboxylic acid

１５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−メトキシ−フェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
１６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロフェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
１７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（４−クロロフェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
１８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（３−メトキシ−フェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
１９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−モルホリン−４−イルメチル−イソオキサゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
２０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（４−メトキシ−フェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
２１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−フェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
２２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロベンゾイルアミノ）−イソオキサゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）

15. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -pentanoic acid (TFA salt)
16. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)
17. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (4-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)
18. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (3-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -pentanoic acid (TFA salt)
19. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-morpholin-4-ylmethyl-isoxazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)
20. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-methoxy-phenyl) -isoxazole-3-carbonyl] -amino} -pentanoic acid (TFA salt)
21. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -isoxazole-3-carbonyl] -amino} -pentanoic acid (TFA salt)
22. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (TFA salt)

２３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（２−フェニル−オキサゾール−５−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

23. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(2-phenyl-oxazole-5-carbonyl) -amino] -pentanoic acid (TFA salt)

２４． （２Ｒ，４Ｒ）−４−［（２−アセチルアミノ−チアゾール−５−カルボニル）−アミノ］−５−ビフェニル−４−イル−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）

24. (2R, 4R) -4-[(2-acetylamino-thiazole-5-carbonyl) -amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid (TFA salt)

２５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［２−（２−メトキシ−ベンゾイルアミノ）−チアゾール−４−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）

25. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[2- (2-methoxy-benzoylamino) -thiazole-4-carbonyl] -amino} -pentanoic acid (TFA salt)

２６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［３−（２−クロロフェニル）−［１，２，４］オキサジアゾール−５−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸

26. (2R, 4R) -5-Biphenyl-4-yl-4-{[3- (2-chlorophenyl)-[1,2,4] oxadiazole-5-carbonyl] -amino} -2-hydroxy-pentane acid

２７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−オキソ−４，５−ジヒドロ−［１，２，４］オキサジアゾール−３−カルボニル）−アミノ］−ペンタン酸。

27. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-oxo-4,5-dihydro- [1,2,4] oxadiazole-3-carbonyl) -amino] -Pentanoic acid.

(Example 13)
These were prepared as parent compounds or as TFA salts.

１． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−ピラジン−２−カルボン酸（ＴＦＡ塩）

1. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyrazine-2-carboxylic acid (TFA salt)

２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（ピリミジン−５−カルボニル）−アミノ］−ペンタン酸エチルエステル（ＴＦＡ塩）

2. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(pyrimidine-5-carbonyl) -amino] -pentanoic acid ethyl ester (TFA salt)

３． ６−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−ピリダジン−３−カルボン酸（ＴＦＡ塩）
４． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（６−ヒドロキシピリダジン−３−カルボニル）−アミノ］−ペンタン酸エチルエステル
５． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（６−ヒドロキシピリダジン−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

3. 6-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyridazine-3-carboxylic acid (TFA salt)
4). (R) -5-biphenyl-4-yl-2-hydroxy-4-[(6-hydroxypyridazine-3-carbonyl) -amino] -pentanoic acid ethyl ester (R) -5-biphenyl-4-yl-2-hydroxy-4-[(6-hydroxypyridazine-3-carbonyl) -amino] -pentanoic acid (TFA salt)

６． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（６−オキソ−１，４，５，６−テトラヒドロ−ピリダジン−３−カルボニル）−アミノ］−ペンタン酸

6). (R) -5-biphenyl-4-yl-2-hydroxy-4-[(6-oxo-1,4,5,6-tetrahydro-pyridazine-3-carbonyl) -amino] -pentanoic acid

７． ６−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）ニコチン酸

7). 6-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) nicotinic acid

８． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−ピリジン−２−カルボン酸。

8). 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -pyridine-2-carboxylic acid.

(Example 14)
This was prepared as the parent compound.

１．（Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−テトラゾール−５−カルボニル）アミノ］ペンタン酸。

1. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H-tetrazol-5-carbonyl) amino] pentanoic acid.

(Example 15)
These were prepared as TFA salts.

１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−ピラゾール−３−カルボニル）アミノ］ペンタン酸
２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−カルボキシメチル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸
３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ヒドロキシメチル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−メトキシメチル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
５． ５−（（１Ｒ，３Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−２−メチル−２Ｈ−ピラゾール−３−カルボン酸
６． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−２−（４−クロロ−３−トリフルオロメチルスルファニル−ベンジル）−２Ｈ−ピラゾール−３−カルボン酸
７． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシプロピルカルバモイル）−２−（３−クロロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
８． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（４−クロロ−２，６−ジフルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
９． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（２−クロロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１０． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（２−クロロ−５−フルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１１． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（３−クロロ−５−フルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１２． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（４−クロロ−３−トリフルオロメトキシベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１３． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（４−クロロ−２−フルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１４． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（３−クロロ−４−フルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１５． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（４−クロロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１６． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（３−クロロ−２，６−ジフルオロベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１７． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−カルボキシ−３−ヒドロキシ−プロピルカルバモイル）−２−（３−メトキシ−ベンジル）−２Ｈ−ピラゾール−３−カルボン酸
１８． ５−（（Ｒ）−１−ビフェニル−４−イルメチル−３−エトキシカルボニル−３−ヒドロキシ−プロピルカルバモイル）−２Ｈ−ピラゾール−３−カルボン酸エチルエステル
１９． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−メチル−１Ｈ−ピラゾール−３−カルボニル）アミノ］ペンタン酸
２０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−４−イル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
２１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−３−イル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
２２． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピラジン−２−イル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−ペンタン酸
２３． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１’−メチル−２Ｈ，１’Ｈ−［３，４’］ビピラゾリル−５−カルボニル）アミノ］−ペンタン酸
２４． （Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロフェニル）−１Ｈ−ピラゾール−３−カルボニル］アミノ｝−２−ヒドロキシ−ペンタン酸
２５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（３−クロロフェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
２６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２，４−ジクロロフェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
２７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２，５−ジクロロフェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
２８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−フェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
２９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−フェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸エチルエステル
３０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［１−（２，３−ジヒドロキシ−プロピル）−５−（２−ヒドロキシ−フェニル）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
３１． （Ｒ）−４−｛［５−（３−アセチルアミノ−フェニル）−１Ｈ−ピラゾール−３−カルボニル］アミノ｝−５−ビフェニル−４−イル−２−ヒドロキシペンタン酸
３２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−メトキシ−ベンゾイルアミノ）−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
３３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−フェニル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
３４． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１−メチル−５−フェニル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−ペンタン酸
３５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（１−カルボキシメチル−５−フェニル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
３６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［１−（２−カルボキシ−エチル）−５−フェニル−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
３７． （Ｒ）−５−ビフェニル−４−イル−４−［（５−フラン−２−イル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸
３８． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ナフタレン−２−イル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−ペンタン酸
３９． （Ｒ）−５−ビフェニル−４−イル−４−［（５−ビフェニル−４−イル−１Ｈ−ピラゾール−３−カルボニル）アミノ］−２−ヒドロキシ−ペンタン酸
４０． （Ｒ）−５−ビフェニル−４−イル−４−｛［５−（４−クロロフェニル）−１Ｈ−ピラゾール−３−カルボニル］アミノ｝−２−ヒドロキシ−ペンタン酸
４１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（１−ヒドロキシ−１−メチルエチル）−１Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸 ５−メチル−２−オキソ−［１，３］ジオキソール−４−イルメチルエステル

1. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1H-pyrazole-3-carbonyl) amino] pentanoic acid (2R, 4R) -5-biphenyl-4-yl-4-[(5-carboxymethyl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-hydroxymethyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-methoxymethyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid 5-((1R, 3R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2-methyl-2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2- (4-chloro-3-trifluoromethylsulfanyl-benzyl) -2H-pyrazole-3-carvone Acid 7. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxypropylcarbamoyl) -2- (3-chlorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-2,6-difluorobenzyl) -2H-pyrazole-3-carboxylic acid 9. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (2-chlorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (2-chloro-5-fluorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-5-fluorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-3-trifluoromethoxybenzyl) -2H-pyrazole-3-carboxylic acid 13. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chloro-2-fluorobenzyl) -2H-pyrazole-3-carboxylic acid 15. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-4-fluorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (4-chlorobenzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-chloro-2,6-difluorobenzyl) -2H-pyrazole-3-carboxylic acid 17. 18. 5-((R) -1-biphenyl-4-ylmethyl-3-carboxy-3-hydroxy-propylcarbamoyl) -2- (3-methoxy-benzyl) -2H-pyrazole-3-carboxylic acid 5-((R) -1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-3-hydroxy-propylcarbamoyl) -2H-pyrazole-3-carboxylic acid ethyl ester (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-methyl-1H-pyrazole-3-carbonyl) amino] pentanoic acid20. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-4-yl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid 21. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-3-yl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-pyrazin-2-yl-1H-pyrazole-3-carbonyl) amino] -pentanoic acid (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1'-methyl-2H, 1'H- [3,4 '] bipyrazolyl-5-carbonyl) amino] -pentanoic acid 24. (R) -5-biphenyl-4-yl-4-{[5- (2-chlorophenyl) -1H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-chlorophenyl) -1H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-biphenyl-4-yl-4-{[5- (2,4-dichlorophenyl) -1H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2,5-dichlorophenyl) -1H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 28. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -1H-pyrazole-3-carbonyl] -amino} -pentanoic acid 29. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-phenyl) -1H-pyrazole-3-carbonyl] -amino} -pentanoic acid ethyl ester (2R, 4R) -5-Biphenyl-4-yl-4-{[1- (2,3-dihydroxy-propyl) -5- (2-hydroxy-phenyl) -1H-pyrazole-3-carbonyl] -amino } -2-Hydroxy-pentanoic acid 31. (R) -4-{[5- (3-Acetylamino-phenyl) -1H-pyrazole-3-carbonyl] amino} -5-biphenyl-4-yl-2-hydroxypentanoic acid32. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -1H-pyrazole-3-carbonyl] -amino} -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-phenyl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid 34. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(1-methyl-5-phenyl-1H-pyrazole-3-carbonyl) amino] -pentanoic acid 35. (2R, 4R) -5-biphenyl-4-yl-4-[(1-carboxymethyl-5-phenyl-1H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-{[1- (2-carboxy-ethyl) -5-phenyl-1H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 37. (R) -5-biphenyl-4-yl-4-[(5-furan-2-yl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid38. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-naphthalen-2-yl-1H-pyrazole-3-carbonyl) amino] -pentanoic acid 39. (R) -5-biphenyl-4-yl-4-[(5-biphenyl-4-yl-1H-pyrazole-3-carbonyl) amino] -2-hydroxy-pentanoic acid (R) -5-biphenyl-4-yl-4-{[5- (4-chlorophenyl) -1H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid 41. (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (1-hydroxy-1-methylethyl) -1H-pyrazole-3-carbonyl] amino} pentanoic acid 5-methyl 2-Oxo- [1,3] dioxol-4-ylmethyl ester

４２． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（３−ヒドロキシピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
４３． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（３−カルバモイルピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸エチルエステル
４４． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（３−カルバモイルピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（３−カルバモイルピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸エチルエステル
４６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（３−カルバモイルピロリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（４−ヒドロキシピペリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸エチルエステル
４８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（４−ヒドロキシピペリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
４９． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（４−ヒドロキシピペリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−ペンタン酸エチルエステル
５０． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（４−ヒドロキシピペリジン−１−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
５１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（モルホリン−４−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸エチルエステル
５２． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−シクロプロピルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシペンタン酸エチルエステル
５３． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（モルホリン−４−カルボニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸
５４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−シクロプロピルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシペンタン酸エチルエステル
５５． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−シクロプロピルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシペンタン酸
５６． （Ｒ）−５−ビフェニル−４−イル−４−｛［５−（カルボキシメチル−カルバモイル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
５７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−シクロプロピルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシペンタン酸
５８． （Ｒ）−５−ビフェニル−４−イル−４−［（５−カルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸エチルエステル
５９． （Ｒ）−５−ビフェニル−４−イル−４−［（５−カルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
６０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−メチルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］ペンタン酸
６１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−プロピルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］ペンタン酸
６２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−ジメチルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸エチルエステル
６３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−ジメチルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
６４． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（イソブチル−メチル−カルバモイル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸エチルエステル
６５． （２Ｓ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（イソブチルメチル−カルバモイル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−ペンタン酸
６６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（イソブチルメチル−カルバモイル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−ペンタン酸エチルエステル
６７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（イソブチルメチル−カルバモイル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−ペンタン酸
６８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［２−（１Ｈ−イミダゾール−４−イル）−エチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸エチルエステル
６９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［２−（３Ｈ−イミダゾール−４−イル）−エチルカルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝アミノ）ペンタン酸
７０． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−エチルカルバモイル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
７１． （Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−ジメチルアミノ−エチルカルバモイル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
７２． （Ｒ）−５−ビフェニル−４−イル−４−［（５−シクロプロピル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
７３． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−イソプロピル−２Ｈ−ピラゾール−３−カルボニル）アミノ］−ペンタン酸
７４． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−プロピル−２Ｈ−ピラゾール−３−カルボニル）アミノ］−ペンタン酸
７５． （Ｒ）−５−ビフェニル−４−イル−４−［（５−ブチル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
７６． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−フェニル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
７７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［２−（２−カルボキシ−エチル）−５−フェニル−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
７８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［２−（２，３−ジヒドロキシ−プロピル）−５−（２−ヒドロキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
７９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−メトキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
８０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２，５−ジメトキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
８１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−トリフルオロメチル−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
８２． （Ｒ）−５−ビフェニル−４−イル−４−｛［５−（４−フルオロフェニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−２−ヒドロキシ−ペンタン酸
８３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（４−クロロフェニル）−２Ｈ−ピラゾール−３−カルボニル］−
８４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロフェニル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝−２−ヒドロキシ−ペンタン酸
８５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロフェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸エチルエステル
８６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（５−フルオロ−２−メトキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
８７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（５−フルオロ−２−メトキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸イソプロピルエステル（ＨＣＬ塩）
８８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（５−フルオロ−２−メトキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸エチルエステル
８９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（５−メチルチオフェン−２−イル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
９０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（５−クロロチオフェン−２−イル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
９１． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−プロピオニルアミノ−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
９２． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ペンタノイルアミノ−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
９３． （Ｒ）−５−ビフェニル−４−イル−４−［（５−エトキシカルボニルアミノ−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
９４． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−メトキシ−アセチルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
９５． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（２−メトキシ−ベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
９６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
９７． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸エチルエステル
９８． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸イソブチルエステル
９９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−｛［５−（２−クロロベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸イソプロピルエステル
１００． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−（｛５−［（ピリジン−２−カルボニル）−アミノ］−２Ｈ−ピラゾール−３−カルボニル｝−アミノ）−ペンタン酸
１０１． （Ｒ）−４−［（５−アミノ−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−５−ビフェニル−４−イル−２−ヒドロキシ−ペンタン酸
１０２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
１０３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸エチルエステル
１０４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
１０５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸 ５−メチル−２−オキソ−［１，３］ジオキソール−４−イルメチルエステル
１０６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−ピラジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］ペンタン酸
１０７． （２Ｒ，４Ｒ）−４−［（５−アセチル−２Ｈ−ピラゾール−３−カルボニル）アミノ］−５−ビフェニル−４−イル−２−ヒドロキシ−ペンタン酸 １−シクロヘキシルオキシカルボニルオキシエチルエステル
１０８． ５−アセチル−２Ｈ−ピラゾール−３−カルボン酸（（１Ｒ，３Ｒ）−１−ビフェニル−４−イルメチル−３−カルバモイル−３−ヒドロキシプロピル）アミド
１０９． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（（Ｓ）−１−ヒドロキシエチル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸
１１０． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−｛［５−（（Ｒ）−１−ヒドロキシエチル）−２Ｈ−ピラゾール−３−カルボニル］アミノ｝ペンタン酸
１１１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−｛１−［（Ｅ）−ヒドロキシイミノ］−エチル｝−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
１１２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（５−ブチル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸

42. (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (3-hydroxypyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 43. (2S, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ethyl ester Ester 44. (2S, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 45 . (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ethyl ester Ester 46. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (3-carbamoylpyrrolidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 47 . (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -ethyl pentanoate Ester 48. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 49 . (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3-carbonyl] amino} -pentanoic acid ethyl ester 50. (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (4-hydroxypiperidine-1-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 51 . (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (morpholin-4-carbonyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid ethyl ester 52. (2S, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid ethyl ester (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (morpholine-4-carbonyl) -2H-pyrazole-3-carbonyl] amino} pentanoic acid 54. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid ethyl ester (2S, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid (R) -5-biphenyl-4-yl-4-{[5- (carboxymethyl-carbamoyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-[(5-cyclopropylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxypentanoic acid (R) -5-biphenyl-4-yl-4-[(5-carbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid ethyl ester 59. (R) -5-biphenyl-4-yl-4-[(5-carbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-methylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-propylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid 62. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid ethyl ester (2R, 4R) -5-biphenyl-4-yl-4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid (2S, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (isobutyl-methyl-carbamoyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid ethyl ester (2S, 4R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -pentanoic acid ethyl ester (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (isobutylmethyl-carbamoyl) -2H-pyrazole-3-carbonyl] amino} -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5- [2- (1H-imidazol-4-yl) -ethylcarbamoyl] -2H-pyrazol-3-carbonyl} amino ) Pentanoic acid ethyl ester 69. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-({5- [2- (3H-imidazol-4-yl) -ethylcarbamoyl] -2H-pyrazole-3-carbonyl} amino ) Pentanoic acid 70. (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (2-hydroxy-ethylcarbamoyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 71. 72. (R) -5-Biphenyl-4-yl-4-{[5- (2-dimethylamino-ethylcarbamoyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (R) -5-biphenyl-4-yl-4-[(5-cyclopropyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid 73. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-isopropyl-2H-pyrazole-3-carbonyl) amino] -pentanoic acid 74. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-propyl-2H-pyrazole-3-carbonyl) amino] -pentanoic acid (R) -5-biphenyl-4-yl-4-[(5-butyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-phenyl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 77. (2R, 4R) -5-Biphenyl-4-yl-4-{[2- (2-carboxy-ethyl) -5-phenyl-2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 78. (2R, 4R) -5-Biphenyl-4-yl-4-{[2- (2,3-dihydroxy-propyl) -5- (2-hydroxy-phenyl) -2H-pyrazole-3-carbonyl] -amino } -2-Hydroxy-pentanoic acid 79. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2,5-dimethoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 81. (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (2-trifluoromethyl-phenyl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 82. (R) -5-biphenyl-4-yl-4-{[5- (4-fluorophenyl) -2H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid 83. (2R, 4R) -5-biphenyl-4-yl-4-{[5- (4-chlorophenyl) -2H-pyrazole-3-carbonyl]-
84. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -2H-pyrazole-3-carbonyl] amino} -2-hydroxy-pentanoic acid 85. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorophenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ethyl ester (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 87. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid Isopropyl ester (HCL salt)
88. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-fluoro-2-methoxy-phenyl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid Ethyl ester 89. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5- (5-methylthiophen-2-yl) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 90 . (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (5-chlorothiophen-2-yl) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 91 . (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-propionylamino-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 92. (R) -5-biphenyl-4-yl-2-hydroxy-4-[(5-pentanoylamino-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 93. (R) -5-biphenyl-4-yl-4-[(5-ethoxycarbonylamino-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid 94. (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-acetylamino) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 95. (R) -5-biphenyl-4-yl-2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -2H-pyrazole-3-carbonyl] -amino} -pentanoic acid 96. (2R, 4R) -5-biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 97. 98. (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid ethyl ester (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid isobutyl ester (2R, 4R) -5-Biphenyl-4-yl-4-{[5- (2-chlorobenzoylamino) -2H-pyrazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid isopropyl ester (R) -5-biphenyl-4-yl-2-hydroxy-4-({5-[(pyridine-2-carbonyl) -amino] -2H-pyrazole-3-carbonyl} -amino) -pentanoic acid 101. (R) -4-[(5-Amino-2H-pyrazole-3-carbonyl) -amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid 102. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 103. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid ethyl ester (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid isobutyl ester (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid 5-methyl-2- Oxo- [1,3] dioxol-4-ylmethyl ester 106. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazole-3-carbonyl) -amino] pentanoic acid (2R, 4R) -4-[(5-Acetyl-2H-pyrazole-3-carbonyl) amino] -5-biphenyl-4-yl-2-hydroxy-pentanoic acid 1-cyclohexyloxycarbonyloxyethyl ester 5-acetyl-2H-pyrazole-3-carboxylic acid ((1R, 3R) -1-biphenyl-4-ylmethyl-3-carbamoyl-3-hydroxypropyl) amide 109. (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5-((S) -1-hydroxyethyl) -2H-pyrazole-3-carbonyl] amino} pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-{[5-((R) -1-hydroxyethyl) -2H-pyrazole-3-carbonyl] amino} pentanoic acid (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[(5- {1-[(E) -hydroxyimino] -ethyl} -2H-pyrazole-3-carbonyl) -amino] -Pentanoic acid 112. (2R, 4R) -5-Biphenyl-4-yl-4-[(5-butyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

１１３． （Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１Ｈ−ピラゾール−４−カルボニル）アミノ］ペンタン酸
（実施例１６）
本明細書中の実施例に記載された手順に従い、適当な出発物質および試薬を代わりに使用して、以下の式を有する化合物をＴＦＡ塩として調製した。

113. (R) -5-Biphenyl-4-yl-2-hydroxy-4-[(1H-pyrazole-4-carbonyl) amino] pentanoic acid (Example 16)
Following the procedures described in the examples herein, using the appropriate starting materials and reagents instead, a compound having the following formula was prepared as a TFA salt.

１． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−４−［（４，５−ジヒドロ−６−オキサ−３，３ａ−ジアザ−ベンゾ［ｅ］アズレン−２−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
２． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（８−オキサ−１１，１４−ジアザ−トリシクロ［９．２．１．０２，７］テトラデカ−１（１４），２，４，６，１２−ペンタエン−１２−カルボニル）−アミノ］−ペンタン酸
３． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１０−オキサ−５，６−ジアザ−トリシクロ［９．４．０．０２，６］ペンタデカ−１（１５），２，４，１１，１３−ペンタエン−４−カルボニル）−アミノ］−ペンタン酸
４． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（（Ｓ）−８−ヒドロキシ−１０−オキサ−５，６−ジアザ−トリシクロ［９．４．０．０２，６］ペンタデカ−１（１５），２，４，１１，１３−ペンタエン−４−カルボニル）−アミノ］−ペンタン酸
５． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（（Ｒ）−８−ヒドロキシ−１０−オキサ−５，６−ジアザ−トリシクロ［９．４．０．０２，６］ペンタデカ−１（１５），２，４，１１，１３−ペンタエン−４−カルボニル）−アミノ］−ペンタン酸
６． （２Ｒ，４Ｒ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（５−オキサ−３，３ａ−ジアザ−シクロペンタ［ａ］ナフタレン−２−カルボニル）−アミノ］−ペンタン酸。

1. (2R, 4R) -5-Biphenyl-4-yl-4-[(4,5-dihydro-6-oxa-3,3a-diaza-benzo [e] azulene-2-carbonyl) -amino] -2- Hydroxy-pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(8-oxa-11,14-diaza-tricyclo [9.2.1.02,7] tetradeca-1 (14) 2,4,6,12-pentaene-12-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(10-oxa-5,6-diaza-tricyclo [9.4.0.02,6] pentadeca-1 (15) , 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[((S) -8-hydroxy-10-oxa-5,6-diaza-tricyclo [9.4.0.02, 6] pentadeca-1 (15), 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-biphenyl-4-yl-2-hydroxy-4-[((R) -8-hydroxy-10-oxa-5,6-diaza-tricyclo [9.4.0.02, 6] pentadeca-1 (15), 2,4,11,13-pentaene-4-carbonyl) -amino] -pentanoic acid (2R, 4R) -5-Biphenyl-4-yl-2-hydroxy-4-[(5-oxa-3,3a-diaza-cyclopenta [a] naphthalene-2-carbonyl) -amino] -pentanoic acid.

Preparation 9
(S) -2- (4-Bromobenzyl) -5-oxopyrrolidine-1-carboxylic acid t-butyl ester

（Ｒ）−２−アミノ−３−（４−ブロモフェニル）プロピオン酸（５０ｇ、０．２モル）のＭｅＣＮ（７００ｍＬ）溶液に、ＮａＯＨ（１６．４ｇ、０．４モル）の水（７００ｍＬ）溶液を−５℃で加えた。１０分間撹拌後、（Ｂｏｃ）_２Ｏ（４４．７ｇ、０．２モル）のＭｅＣＮ（１００ｍＬ）溶液を加えた。この混合物を室温に温め、一晩撹拌した。ＭｅＣＮの蒸発後、残渣をＤＣＭ（８００ｍＬ）で希釈し、−５℃で、１Ｍ ＨＣｌでｐＨ＝２に酸性化した。この水性物質をＤＣＭ（３×２００ｍＬ）で抽出した。合わせた有機層を飽和水性ＮａＣｌ（５００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮することによって、白色の固体として、化合物１を得た（６６．５ｇ）。ＬＣ−ＭＳ：３６６（Ｍ＋Ｎａ）、７０９（２Ｍ＋Ｎａ）。

To a solution of (R) -2-amino-3- (4-bromophenyl) propionic acid (50 g, 0.2 mol) in MeCN (700 mL), NaOH (16.4 g, 0.4 mol) in water (700 mL). The solution was added at -5 ° C. After stirring for 10 minutes, a solution of (Boc) ₂ O (44.7 g, 0.2 mol) in MeCN (100 mL) was added. The mixture was warmed to room temperature and stirred overnight. After evaporation of MeCN, the residue was diluted with DCM (800 mL) and acidified to pH = 2 with 1M HCl at −5 ° C. This aqueous material was extracted with DCM (3 × 200 mL). The combined organic layers were washed with saturated aqueous NaCl (500 mL), dried over Na ₂ SO ₄ and concentrated to give compound 1 as a white solid (66.5 g). LC-MS: 366 (M + Na), 709 (2M + Na).

To a solution of Compound 1 (66.5 g, 193 μmol), Meldrum acid (33.4 g, 232 mmol) and DMAP (37.7 g, 309 mmol) in anhydrous DCM (600 mL) was added DCC (47.9 g, 232 mmol) in anhydrous DCM (200 mL). ) The solution was added dropwise at -5 ° C over 1 hour under nitrogen. The mixture was stirred at −5 ° C. for 8 hours and then refrigerated overnight. Crystals of dicyclohexylurea were observed. The mixture was filtered, washed with 5% KHSO ₄ (5 × 200 mL), saturated aqueous NaCl (200 mL), and dried over anhydrous MgSO ₄ overnight under refrigeration. The solution was then evaporated to give crude compound 2 (91 g) as a pale yellow solid. LC-MS: 492 (M + Na), 961 (2M + Na).

粗製の化合物２（９１ｇ、１９３ｍｍｏｌ）の無水ＤＣＭ（１Ｌ）溶液に、窒素下−５℃で、ＡｃＯＨ（１２７．５ｇ、２．１モル）を加えた。この混合物を−５℃で３０分間撹拌し、次いでＮａＢＨ_４（１８．３ｇ、４８３ｍｍｏｌ）を１時間にわたり少量ずつ加えた。もう１時間−５℃で撹拌後、飽和水性ＮａＣｌ（５００ｍＬ）を加えた。有機層を、飽和水性ＮａＣｌ（２×３００ｍＬ）および水（２×３００ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、濃縮することによって、粗生成物を得た。これをＥｔ_２Ｏで洗浄してさらに精製することによって、淡黄色の固体として、化合物３を得た（６８ｇ）。ＬＣ−ＭＳ：４７８（Ｍ＋Ｎａ）、９３３（２Ｍ＋Ｎａ）。

AcOH (127.5 g, 2.1 mol) was added to a solution of crude compound 2 (91 g, 193 mmol) in anhydrous DCM (1 L) at −5 ° C. under nitrogen. The mixture was stirred at −5 ° C. for 30 minutes, then NaBH ₄ (18.3 g, 483 mmol) was added in portions over 1 hour. After stirring for another hour at −5 ° C., saturated aqueous NaCl (500 mL) was added. The organic layer was washed with saturated aqueous NaCl (2 × 300 mL) and water (2 × 300 mL), dried over MgSO ₄ , filtered and concentrated to give the crude product. This was washed with Et ₂ O and further purified to obtain Compound 3 as a pale yellow solid (68 g). LC-MS: 478 (M + Na), 933 (2M + Na).

  A solution of compound 3 (68 g, 149 mmol) in anhydrous toluene (500 mL) was refluxed under nitrogen for 3 hours. After evaporation of the solvent, the residue was purified by chromatography (hexane: EtOAc = 10: 1) to give the title compound as a pale yellow oil (38 g). LC-MS: 376 (M + Na), 729 (2M + Na).

Preparation 10
(2R, 4R) -4-Amino-5- (4-bromophenyl) -2-hydroxypentanoic acid ethyl ester

（Ｓ）−２−（４−ブロモベンジル）−５−オキソピロリジン−１−カルボン酸ｔ−ブチルエステル（３８ｇ、１０７ｍｍｏｌ）の無水ＤＣＭ（２５０ｍＬ）溶液に、窒素下、−５℃でＴＦＡ（２０ｍＬ、０．２７モル）を加えた。この混合物を室温に温め、一晩撹拌した。溶媒の蒸発後、残渣をＥｔＯＡｃ（３００ｍＬ）で希釈し、飽和水性ＮａＨＣＯ_３（３×２００ｍＬ）、水（２００ｍＬ）で洗浄し、飽和水性ＮａＣｌ（２５０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮することによって、淡黄色の固体として、粗製の化合物１を得た（２４ｇ）。ＬＣ−ＭＳ：２５４（Ｍ＋Ｈ）。

To a solution of (S) -2- (4-bromobenzyl) -5-oxopyrrolidine-1-carboxylic acid t-butyl ester (38 g, 107 mmol) in anhydrous DCM (250 mL) at −5 ° C. under nitrogen at −5 ° C. 0.27 mol) was added. The mixture was warmed to room temperature and stirred overnight. After evaporation of the solvent, the residue was diluted with EtOAc (300 mL), washed with saturated aqueous NaHCO ₃ (3 × 200 mL), water (200 mL), washed with saturated aqueous NaCl (250 mL) and dried over Na ₂ SO _4. To give crude compound 1 as a pale yellow solid (24 g). LC-MS: 254 (M + H).

To a solution of NaH (8.6 g, 250 mmol) in anhydrous THF (200 mL), a solution of compound 1 (24 g, 94 mmol) in anhydrous THF (200 mL) was added dropwise at 0 ° C. over 30 minutes under nitrogen. The mixture was warmed to room temperature and stirred for 2 hours. After cooling to 0 ° C., pivaloyl chloride (18 g, 150 mmol) was added dropwise over 30 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated aqueous NH ₄ Cl (300 mL) and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over MgSO ₄ , filtered and concentrated to give the crude product. This was further purified by chromatography (hexane: EtOAc = 25: 1) to give compound 2 (18 g) as a pale yellow solid. LC-MS: 360 (M + Na).

化合物２（１８ｇ、５３ｍｍｏｌ）の無水ＴＨＦ（２５０ｍＬ）溶液に、窒素下、−７８℃で３０分間にわたりＨＭＤＳＮａ（４７．７ｍＬ、９６ｍｍｏｌ）を滴下添加した。−７８℃で９０分間撹拌後、（＋）−（８，８−ジクロロカンフォリルスルホニル）オキサジリジン（３１．６ｇ、１０６ｍｍｏｌ）の溶液を３０分間にわたり滴下添加した。−７８℃で２時間撹拌後、この反応を飽和水性ＮＨ_４Ｃｌ（４００ｍＬ）でクエンチし、ＥｔＯＡｃ（３×３００ｍＬ）で抽出した。合わせた有機層を飽和水性ＮａＣｌ（３００ｍＬ）で洗浄し、ＭｇＳＯ_４で乾燥させ、濾過し、濃縮することによって、粗生成物を得た。これをクロマトグラフィー（ヘキサン：ＥｔＯＡｃ＝１５：１）でさらに精製することによって、淡黄色の固体として、化合物３（８．９ｇ）を得た。ＬＣ−ＭＳ：３７６（Ｍ＋Ｎａ）。

HMDSNa (47.7 mL, 96 mmol) was added dropwise to a solution of compound 2 (18 g, 53 mmol) in anhydrous THF (250 mL) at −78 ° C. over 30 minutes under nitrogen. After stirring at −78 ° C. for 90 minutes, a solution of (+)-(8,8-dichlorocamphorylsulfonyl) oxaziridine (31.6 g, 106 mmol) was added dropwise over 30 minutes. After stirring at −78 ° C. for 2 hours, the reaction was quenched with saturated aqueous NH ₄ Cl (400 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated aqueous NaCl (300 mL), dried over MgSO ₄ , filtered and concentrated to give the crude product. This was further purified by chromatography (hexane: EtOAc = 15: 1) to give compound 3 (8.9 g) as a pale yellow solid. LC-MS: 376 (M + Na).

A solution of compound 3 (8.9 g, 25 mmol) in concentrated HCl (81 mL, 81 mmol) was heated at 100 ° C. for 16 hours. The mixture was then concentrated to give a crude product. This was washed with Et ₂ O and further purified to obtain Compound 4 (7 g) as a pale yellow solid HCl salt. LC-MS: 323 (M + H).

A solution of compound 4 (7 g, 22 mmol) in EtOH (10 mL) was mixed with 8 M HCl in EtOH (120 mL, 960 mmol) at room temperature. The mixture was heated at 50 ° C. for 16 hours and then concentrated. The crude product was washed with Et ₂ O and further purified to give the title compound as a pale yellow solid HCl salt (6 g). LC-MS: 352 (M + H).

Preparation 11
1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid

１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボン酸エチルエステル（２．０ｇ、１３ｍｍｏｌ）およびＥｔＯＨ（２５ｍＬ）を、水酸化リチウム一水和物（１．６ｇ、３８．２ｍｍｏｌ）および水（１０ｍＬ）の予め溶解させた溶液と混合し、室温で４時間撹拌した。この混合物を部分的に濃縮し、ＨＣｌで酸性化することによって、沈殿を引き起こした。この固体を濾過し、真空下で乾燥させることによって、表題化合物を得た（１．３ｇ）。

1-hydroxy-1H- [1,2,3] triazole-4-carboxylic acid ethyl ester (2.0 g, 13 mmol) and EtOH (25 mL) were added to lithium hydroxide monohydrate (1.6 g, 38.2 mmol). ) And water (10 mL) in a pre-dissolved solution and stirred at room temperature for 4 hours. The mixture was partially concentrated and acidified with HCl to cause precipitation. The solid was filtered and dried under vacuum to give the title compound (1.3 g).

Preparation 12
(2R, 4R) -5- (4-Bromo-phenyl) -2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester

１−ヒドロキシ−１Ｈ−１，２，３−トリアゾール−４−カルボン酸（１６３ｍｇ、１．３ｍｍｏｌ）、）、ＨＣＴＵ（５２３ｍｇ、１．３ｍｍｏｌ）、およびＤＭＦを混合し、室温で５分間撹拌した。ＤＩＰＥＡ（６６１μＬ、３．８ｍｍｏｌ）および（２Ｒ，４Ｒ）−４−アミノ−５−（４−ブロモフェニル）−２−ヒドロキシペンタン酸エチルエステル（４ｍｇ、１．３ｍｍｏｌ）を加え、生成した混合物を１０分間撹拌した。この反応混合物を減圧下で蒸発させ、精製する（Ｃ１８カラム；０．０５％ＴＦＡを加えた、水中２０〜７０％ＭｅＣＮ）ことによって、表題化合物を得た（３３０ｍｇ）。

1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (163 mg, 1.3 mmol),), HCTU (523 mg, 1.3 mmol), and DMF were mixed and stirred at room temperature for 5 minutes. DIPEA (661 μL, 3.8 mmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxypentanoic acid ethyl ester (4 mg, 1.3 mmol) were added and the resulting mixture was added 10 Stir for minutes. The reaction mixture was evaporated under reduced pressure and purified (C18 column; 20-70% MeCN in water with addition of 0.05% TFA) to give the title compound (330 mg).

(Example 17)
A. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] Pentanoic acid

１−ヒドロキシ−１Ｈ−１，２，３−トリアゾール−４−カルボン酸（１７．６ｍｇ、１３６μｍｏｌ）およびＨＣＴＵ（５６．４ｍｇ、１３６μｍｏｌ）をＤＭＦ中で混合し、室温で５分間撹拌した。ＤＩＰＥＡ（７１．２μｌ、４０９μｍｏｌ）および（２Ｒ，４Ｒ）−４−アミノ−５−（４−ブロモフェニル）−２−ヒドロキシペンタン酸エチルエステル（４３ｍｇ、１４０μｍｏｌ）を加え、生成した混合物を１０分間撹拌した。この反応混合物を減圧下で蒸発させ、精製した（Ｃ１８逆相カラム）。精製した物質を３−クロロフェニルボロン酸、ピナコールエステル（４８．１ｍｇ、２０２μｍｏｌ）、Ｋ_２ＣＯ_３（４１．８ｍｇ、３０２μｍｏｌ）、ＥｔＯＨ（１ｍｌ）および水（０．３ｍｌ）と混合した。酸素を除去し（高真空）、ＳｉｌｉｃａＣａｔ（登録商標）Ｐｄ（０）（０．０９ｍｍｏｌ／ｇで充填；１１２ｍｇ、１０．１μｍｏｌ）を窒素下で急速に加えた。この混合物を１００℃で２０分間マイクロ波処理し、次いで濃縮した。この物質をＡｃＯＨ中に再び溶解させ、分取ＨＰＬＣで精製することによって、表題化合物を得た（１２ｍｇ；純度９５％）。Ｃ_２０Ｈ_１９ＣｌＮ_４Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４３１．１０；測定値：４３１．４。

1-hydroxy-1H-1,2,3-triazole-4-carboxylic acid (17.6 mg, 136 μmol) and HCTU (56.4 mg, 136 μmol) were mixed in DMF and stirred at room temperature for 5 minutes. DIPEA (71.2 μl, 409 μmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxypentanoic acid ethyl ester (43 mg, 140 μmol) were added and the resulting mixture was stirred for 10 minutes. did. The reaction mixture was evaporated under reduced pressure and purified (C18 reverse phase column). The purified material was mixed with 3-chlorophenylboronic acid, pinacol ester (48.1 mg, 202 μmol), K ₂ CO ₃ (41.8 mg, 302 μmol), EtOH (1 ml) and water (0.3 ml). Oxygen was removed (high vacuum) and SilicaCat® Pd (0) (filled with 0.09 mmol / g; 112 mg, 10.1 μmol) was added rapidly under nitrogen. The mixture was microwaved at 100 ° C. for 20 minutes and then concentrated. This material was redissolved in AcOH and purified by preparative HPLC to give the title compound (12 mg; purity 95%). C ₂₀ H ₁₉ ClN ₄ against _{O 5 MS m / z [M} + H] + Calculated: 431.10; Found: 431.4.

  B. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] Pentanoic acid ethyl ester

（２Ｒ，４Ｒ）−５−（４−ブロモ−フェニル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−１，２，３−トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル（１２０ｍｇ、２８１μｍｏｌ）および３−クロロフェニルボロン酸、ピナコールエステル（１２０ｍｇ、５０６μｍｏｌ）を、Ｋ_２ＣＯ_３（１１６ｍｇ、８４２μｍｏｌ）、ＥｔＯＨ（３ｍＬ）、および水（０．８ｍＬ）と混合した。次いで、ＳｉｌｉｃａＣａｔ（登録商標）ＤＰＰ−Ｐｄ（２８０μｍｏｌ／ｇで充填；１ｍｇ、２８μｍｏｌ）を加え、この混合物を９０℃で加熱し、この反応をＬＣ／ＭＳでモニターした。２時間後、反応が停止し、この混合物を濾過し、濃縮し、精製した（Ｃ１８逆相カラム；０．０５％ＴＦＡを加えた、水中３０〜７０％ＭｅＣＮ）。ＥｔＯＨ（５．０ｍＬ、８６ｍｍｏｌ）およびジオキサン中４ＭのＨＣｌ（１．５ｍＬ、６．０ｍｍｏｌ）を加え、生成した混合物を室温で４０分間撹拌し、次いで濃縮し、精製する（Ｃ１８逆相カラム；０．０５％ＴＦＡを加えた、水中３０〜９０％ＭｅＣＮ）ことによって、表題化合物を得た（２０ｍｇ；純度９５％）。Ｃ_２２Ｈ_２３ＣｌＮ_４Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４５９．１４；測定値：４５９．４。

(2R, 4R) -5- (4-Bromo-phenyl) -2-hydroxy-4-[(1-hydroxy-1H-1,2,3-triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester (120 mg, 281 μmol) and 3-chlorophenylboronic acid, pinacol ester (120 mg, 506 μmol) were mixed with K ₂ CO ₃ (116 mg, 842 μmol), EtOH (3 mL), and water (0.8 mL). SilicaCat® DPP-Pd (packed at 280 μmol / g; 1 mg, 28 μmol) was then added and the mixture was heated at 90 ° C. and the reaction was monitored by LC / MS. After 2 hours the reaction was stopped and the mixture was filtered, concentrated and purified (C18 reverse phase column; 30-70% MeCN in water with 0.05% TFA). EtOH (5.0 mL, 86 mmol) and 4M HCl in dioxane (1.5 mL, 6.0 mmol) were added and the resulting mixture was stirred at room temperature for 40 minutes, then concentrated and purified (C18 reverse phase column; 0 (30-90% MeCN in water with .05% TFA) to give the title compound (20 mg; purity 95%). MS m / z for _{C 22 H 23 ClN 4 O 5} [M + H] + Calculated: 459.14; Found: 459.4.

(Example 18)
Following the procedures described in the Examples herein, the compounds having the following formula were prepared as parent compounds or as TFA salts, using appropriate starting materials and reagents instead.

１． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル（ＴＦＡ塩）

1. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid ethyl ester Esters (TFA salts)

２． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

2. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid ( TFA salt)

３． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸
４． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸エチルエステル

3. (2R, 4R) -5- (3′-chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid ethyl ester

５． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
６． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル

5). (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid isobutyl ester 6 . (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid isopropyl ester

７． （２Ｒ，４Ｒ）−４−［（３−アセチル−イソオキサゾール−５−カルボニル）−アミノ］−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸
８． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−メトキシ−イソオキサゾール−５−カルボニル）−アミノ］−ペンタン酸
９． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−［（３−クロロ−イソオキサゾール−５−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
１０． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−イソプロピル−イソオキサゾール−５−カルボニル）−アミノ］−ペンタン酸
１１． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−プロピル−イソオキサゾール−５−カルボニル）−アミノ］−ペンタン酸
１２． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−イソブチル−イソオキサゾール−５−カルボニル）−アミノ］−ペンタン酸
１３． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−｛［３−（１−ヒドロキシ−１−メチル−エチル）−イソオキサゾール−５−カルボニル］−アミノ｝−ペンタン酸
１４． （２Ｒ，４Ｒ）−４−［（３−ｔｅｒｔ−ブチル−イソオキサゾール−５−カルボニル）−アミノ］−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸

7). (2R, 4R) -4-[(3-acetyl-isoxazole-5-carbonyl) -amino] -5- (3'-chlorobiphenyl-4-yl) -2-hydroxy-pentanoic acid (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3-methoxy-isoxazole-5-carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (3′-chloro-biphenyl-4-yl) -4-[(3-chloro-isoxazole-5-carbonyl) -amino] -2-hydroxy-pentanoic acid (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-isopropyl-isoxazole-5-carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-propyl-isoxazole-5-carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(3-isobutyl-isoxazole-5-carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[3- (1-hydroxy-1-methyl-ethyl) -isoxazole-5-carbonyl] -Amino} -pentanoic acid14. (2R, 4R) -4-[(3-tert-butyl-isoxazol-5-carbonyl) -amino] -5- (3'-chloro-biphenyl-4-yl) -2-hydroxy-pentanoic acid

１５． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−４−｛［５−（２−クロロフェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
１６． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−｛［５−（２−ヒドロキシフェニル）−イソオキサゾール−３−カルボニル］−アミノ｝−ペンタン酸

15. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -4-{[5- (2-chlorophenyl) -isoxazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 16 . (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxyphenyl) -isoxazole-3-carbonyl] -amino} -pentanoic acid

１７． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸（ＴＦＡ塩）
１８． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−｛［５−（２−ヒドロキシ−フェニル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸エチルエステル（ＴＦＡ塩）
１９． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピラジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
２０． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピラジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸エチルエステル
２１． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピラジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
２２． （２Ｓ，４Ｓ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピラジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸 ５−メチル−２−オキソ−［１，３］ジオキソール−４−イルメチルエステル（ＴＦＡ塩）
２３． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
２４． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸エチルエステル
２５． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
２６． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル
２７． （２Ｒ，４Ｒ）−４−｛［５−（２−クロロベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
２８． （２Ｒ，４Ｒ）−４−｛［５−（２−クロロ−ベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸エチルエステル（ＴＦＡ塩）
２９． （２Ｒ，４Ｒ）−４−｛［５−（２−クロロ−ベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸イソブチルエステル（ＴＦＡ塩）
３０． （２Ｒ，４Ｒ）−４−｛［５−（２−クロロ−ベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸イソプロピルエステル（ＴＦＡ塩）
３１． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−｛［５−（２−メトキシ−ベンゾイルアミノ）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
３２． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−｛［５−（１−ヒドロキシ−エチル）−２Ｈ−ピラゾール−３−カルボニル］−アミノ｝−ペンタン酸
３３． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−３−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸エチルエステル（ＴＦＡ塩）

17. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxy-phenyl) -2H-pyrazole-3-carbonyl] -amino}- Pentanoic acid (TFA salt)
18. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-{[5- (2-hydroxy-phenyl) -2H-pyrazole-3-carbonyl] -amino}- Pentanoic acid ethyl ester (TFA salt)
19. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazol-3-carbonyl) -amino] -pentanoic acid (TFA salt)
20. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazol-3-carbonyl) -amino] -pentane Acid ethyl ester 21. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazol-3-carbonyl) -amino] -pentane Acid isobutyl ester 22. (2S, 4S) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyrazin-2-yl-2H-pyrazol-3-carbonyl) -amino] -pentane Acid 5-methyl-2-oxo- [1,3] dioxol-4-ylmethyl ester (TFA salt)
23. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)
24. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentane Acid ethyl ester 25. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentane Acid isobutyl ester 26. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentane Acid isopropyl ester 27. (2R, 4R) -4-{[5- (2-Chlorobenzoylamino) -2H-pyrazol-3-carbonyl] -amino} -5- (3'-chlorobiphenyl-4-yl) -2-hydroxy- Pentanoic acid (TFA salt)
28. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazol-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4-yl) -2- Hydroxy-pentanoic acid ethyl ester (TFA salt)
29. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazol-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4-yl) -2- Hydroxy-pentanoic acid isobutyl ester (TFA salt)
30. (2R, 4R) -4-{[5- (2-Chloro-benzoylamino) -2H-pyrazol-3-carbonyl] -amino} -5- (3'-chloro-biphenyl-4-yl) -2- Hydroxy-pentanoic acid isopropyl ester (TFA salt)
31. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[5- (2-methoxy-benzoylamino) -2H-pyrazole-3-carbonyl] -amino } -Pentanoic acid 32. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-{[5- (1-hydroxy-ethyl) -2H-pyrazole-3-carbonyl] -amino} -Pentanoic acid 33. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-2H-pyrazole-3-carbonyl) -amino] -pentane Acid ethyl ester (TFA salt)

３４． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−３−イル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
３５． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ヒドロキシ−１−メチル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸
３６． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ヒドロキシ−１−メチル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
３７． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ヒドロキシ−１−ピリジン−２−イル−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
３８． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−｛［１−（２−フルオロ−フェニル）−５−ヒドロキシ−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
３９． （２Ｒ，４Ｓ）−５−（３’−クロロ−ビフェニル−４−イル）−４−｛［１−（３−クロロ−フェニル）−５−ヒドロキシ−１Ｈ−ピラゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４０． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−［（５−エトキシ−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸

34. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-1H-pyrazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)
35. (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl) -amino] -pentane Acid 36. (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-1-methyl-1H-pyrazole-3-carbonyl) -amino] -pentane Acid isobutyl ester 37. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-hydroxy-1-pyridin-2-yl-1H-pyrazole-3-carbonyl)- Amino] -pentanoic acid (TFA salt)
38. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (2-fluoro-phenyl) -5-hydroxy-1H-pyrazole-3-carbonyl] -amino} 2-Hydroxy-pentanoic acid 39. (2R, 4S) -5- (3′-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-hydroxy-1H-pyrazole-3-carbonyl] -amino} 2-hydroxy-pentanoic acid 40. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-[(5-ethoxy-1H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid

４１． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−オキソ−１−フェニル−２，５−ジヒドロ−１Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
４２． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−｛［１−（３−クロロ−フェニル）−５−オキソ−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４３． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−｛［１−（２−クロロ−フェニル）−５−オキソ−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４４． （２Ｒ，４Ｒ）−５−（３’−クロロ−ビフェニル−４−イル）−４−｛［１−（４−フルオロ−フェニル）−５−オキソ−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸

41. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carbonyl) -Amino] -pentanoic acid (TFA salt)
42. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-oxo-4,5-dihydro-1H- [1, 2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 43. (2R, 4R) -5- (3'-Chloro-biphenyl-4-yl) -4-{[1- (2-chloro-phenyl) -5-oxo-4,5-dihydro-1H- [1, 2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid 44. (2R, 4R) -5- (3′-Chloro-biphenyl-4-yl) -4-{[1- (4-fluoro-phenyl) -5-oxo-4,5-dihydro-1H- [1, 2,4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid

４５． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−トリフルオロメチル−４Ｈ−［１，２，４］トリアゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

45. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-trifluoromethyl-4H- [1,2,4] triazole-3-carbonyl)- Amino] -pentanoic acid (TFA salt)

４６． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−４−［（５−クロロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）

46. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -4-[(5-chloro-1H- [1,2,4] triazole-3-carbonyl) -amino] -2-hydroxy -Pentanoic acid (TFA salt)

４７． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（５−オキソ−１−フェニル−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

47. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H- [1,2,4 ] Triazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)

４８． （２Ｒ，４Ｒ）−４−［（１−ベンジル−６−オキソ−１，６−ジヒドロ−ピリダジン−３−カルボニル）−アミノ］−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸（ＴＦＡ塩）
４９． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（６−オキソ−１−フェニル−１，６−ジヒドロ−ピリダジン−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

48. (2R, 4R) -4-[(1-Benzyl-6-oxo-1,6-dihydro-pyridazine-3-carbonyl) -amino] -5- (3'-chlorobiphenyl-4-yl) -2- Hydroxy-pentanoic acid (TFA salt)
49. (2R, 4R) -5- (3′-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(6-oxo-1-phenyl-1,6-dihydro-pyridazine-3-carbonyl) -amino ] -Pentanoic acid (TFA salt)

５０． （２Ｒ，４Ｒ）−５−（３’−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（６−ヒドロキシ−ピリダジン−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）。

50. (2R, 4R) -5- (3'-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(6-hydroxy-pyridazine-3-carbonyl) -amino] -pentanoic acid (TFA salt).

(Example 19)
Following the procedures described in the examples herein, the compound having the following formula was prepared as the parent compound, using appropriate starting materials and reagents instead.

１． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸
２． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
３． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル
４． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル
５． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸ヘプチルエステル
６． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸
７． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
８． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル
９． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル
１０． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸ヘプチルエステル
１１． （２Ｒ，４Ｒ）−４−｛［１−（（Ｓ）−２−アミノ−３−メチル−ブチリルオキシメトキシ）−１Ｈ−［１，２，３］トリアゾール−４−カルボニル］−アミノ｝−５−（５’−クロロ−２’−フルオロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸イソプロピルエステル
１２． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸
１３． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
１４． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル
１５． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸エチルエステル
１６． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸ヘプチルエステル
１７． （２Ｒ，４Ｒ）−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−５−（２’−メトキシ−ビフェニル−４−イル）−ペンタン酸

1. (2R, 4R) -5- (2 ′, 5′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -Amino] -pentanoic acid (2R, 4R) -5- (2 ′, 5′-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl 2.)-Amino] -pentanoic acid isobutyl ester (2R, 4R) -5- (2 ′, 5′-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl ) -Amino] -pentanoic acid isopropyl ester (2R, 4R) -5- (2 ′, 5′-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl 4.)-Amino] -pentanoic acid ethyl ester (2R, 4R) -5- (2 ′, 5′-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl ) -Amino] -pentanoic acid heptyl ester (2R, 4R) -5- (5′-Chloro-2′-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4- 6. Carbonyl) -amino] -pentanoic acid (2R, 4R) -5- (5′-Chloro-2′-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4- 7. Carbonyl) -amino] -pentanoic acid isobutyl ester (2R, 4R) -5- (5′-Chloro-2′-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4- 8. Carbonyl) -amino] -pentanoic acid isopropyl ester (2R, 4R) -5- (5′-Chloro-2′-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4- 9. Carbonyl) -amino] -pentanoic acid ethyl ester (2R, 4R) -5- (5′-Chloro-2′-fluorobiphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4- 11. Carbonyl) -amino] -pentanoic acid heptyl ester (2R, 4R) -4-{[1-((S) -2-Amino-3-methyl-butyryloxymethoxy) -1H- [1,2,3] triazole-4-carbonyl] -amino}- 5- (5′-chloro-2′-fluoro-biphenyl-4-yl) -2-hydroxy-pentanoic acid isopropyl ester (2R, 4R) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] -pentanoic acid13. (2R, 4R) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] -pentanoic acid isobutyl ester14. (2R, 4R) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] -pentanoic acid isopropyl ester15. (2R, 4R) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] -pentanoic acid ethyl ester (2R, 4R) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4 -Carbonyl) -amino] -pentanoic acid heptyl ester (2R, 4R) -2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazol-4-carbonyl) -amino] -5- (2′-methoxy-biphenyl-4-yl) ) -Pentanoic acid

１８． （２Ｒ，４Ｒ）−４−［（３−アセトキシメトキシ−３Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−５−（５’−クロロ−２’−フルオロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸

18. (2R, 4R) -4-[(3-Acetoxymethoxy-3H- [1,2,3] triazole-4-carbonyl) -amino] -5- (5'-chloro-2'-fluoro-biphenyl-4 -Yl) -2-hydroxy-pentanoic acid

１９． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−メトキシ−イソオキサゾール−５−カルボニル）−アミノ］−ペンタン酸

19. (2R, 4R) -5- (5'-Chloro-2'-fluoro-biphenyl-4-yl) -2-hydroxy-4-[(3-methoxy-isoxazole-5-carbonyl) -amino] -pentane acid

２０． （２Ｒ，４Ｒ）−５−（５’−クロロ−２’−フルオロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−オキソ−１−フェニル−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）−アミノ］−ペンタン酸

20. (2R, 4R) -5- (5'-Chloro-2'-fluoro-biphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H- [1,2,4] triazole-3-carbonyl) -amino] -pentanoic acid

２１． （２Ｒ，４Ｒ）−４−［（３−アセトキシメトキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−５−（２’，５’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸
２２． （２Ｒ，４Ｒ）−４−｛［３−（（Ｓ）−２−アミノ−３−メチル−ブチリルオキシメトキシ）−３Ｈ−ベンゾトリアゾール−５−カルボニル］−アミノ｝−５−（３’−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸イソブチルエステル。

21. (2R, 4R) -4-[(3-Acetoxymethoxy-3H-benzotriazole-5-carbonyl) -amino] -5- (2 ', 5'-dichloro-biphenyl-4-yl) -2-hydroxy- Pentanoic acid 22. (2R, 4R) -4-{[3-((S) -2-Amino-3-methyl-butyryloxymethoxy) -3H-benzotriazole-5-carbonyl] -amino} -5- (3'- Chloro-biphenyl-4-yl) -2-hydroxy-pentanoic acid isobutyl ester.

(Example 20)
Following the procedures described in the Examples herein, the compounds having the following formula were prepared as parent compounds or as TFA salts, using appropriate starting materials and reagents instead.

１． （２Ｒ，４Ｒ）−５−（３−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）

1. (2R, 4R) -5- (3-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(1H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid (TFA salt)

２． （２Ｒ，４Ｒ）−５−（３−クロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸

2. (2R, 4R) -5- (3-Chlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) -amino] -pentanoic acid

３． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−４−｛［１−（３−クロロ−フェニル）−５−オキソ−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル］−アミノ｝−２−ヒドロキシ−ペンタン酸
４． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−オキソ−１−フェニル−４，５−ジヒドロ−１Ｈ−［１，２，４］トリアゾール−３−カルボニル）−アミノ］−ペンタン酸

3. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -4-{[1- (3-chloro-phenyl) -5-oxo-4,5-dihydro-1H- [1,2 , 4] triazole-3-carbonyl] -amino} -2-hydroxy-pentanoic acid (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-oxo-1-phenyl-4,5-dihydro-1H- [1,2,4 ] Triazole-3-carbonyl) -amino] -pentanoic acid

５． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−４−［（５−ジメチルカルバモイル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−２−ヒドロキシ−ペンタン酸
６． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−（｛５−［（２−メトキシ−エチル）−メチル−カルバモイル］−２Ｈ−ピラゾール−３−カルボニル｝−アミノ）−ペンタン酸
７． （２Ｒ，４Ｒ）−４−［（５−アセチル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−５−（３−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−ペンタン酸
８． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−３−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）
９． （２Ｒ，４Ｒ）−５−（３−クロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−ピリジン−２−イル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸（ＴＦＡ塩）。

5). (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -4-[(5-dimethylcarbamoyl-2H-pyrazole-3-carbonyl) -amino] -2-hydroxy-pentanoic acid (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-({5-[(2-methoxy-ethyl) -methyl-carbamoyl] -2H-pyrazole-3- 6. Carbonyl} -amino) -pentanoic acid (2R, 4R) -4-[(5-acetyl-2H-pyrazol-3-carbonyl) -amino] -5- (3-chloro-biphenyl-4-yl) -2-hydroxy-pentanoic acid (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-3-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid (TFA salt)
9. (2R, 4R) -5- (3-Chloro-biphenyl-4-yl) -2-hydroxy-4-[(5-pyridin-2-yl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid (TFA salt).

(Example 21)
Following the procedures described in the examples herein, the compound having the following formula was prepared as the parent compound, using appropriate starting materials and reagents instead.

１． （２Ｒ，４Ｒ）−５−（３，３’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ペンタン酸

1. (2R, 4R) -5- (3,3′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3H- [1,2,3] triazole-4-carbonyl) -amino] -pentane acid

２． （２Ｒ，４Ｒ）−５−（３，３’−ジクロロ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（５−メトキシメチル−２Ｈ−ピラゾール−３−カルボニル）−アミノ］−ペンタン酸。

2. (2R, 4R) -5- (3,3′-Dichloro-biphenyl-4-yl) -2-hydroxy-4-[(5-methoxymethyl-2H-pyrazole-3-carbonyl) -amino] -pentanoic acid .

Preparation 13
(2R, 4R) -5- (4-Bromophenyl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid ethyl ester

ＨＣＴＵ（８３７ｍｇ、２．０ｍｍｏｌ）を、１−ヒドロキシ−１Ｈ−１，２，３−ベンゾトリアゾール−６−カルボン酸（３６２ｍｇ、２．０ｍｍｏｌ）の溶液に加え、この混合物を室温で１０分間撹拌した。次いで、ＤＩＰＥＡ（５２９μＬ、３．０ｍｍｏｌ）および（２Ｒ，４Ｒ）−４−アミノ−５−（４−ブロモフェニル）−２−ヒドロキシ−ペンタン酸エチルエステル（３２０ｍｇ、１．０ｍｍｏｌ）を加え、生成した混合物を室温で１５分間撹拌した。この混合物を真空中で濃縮し、生成した残渣を精製する（Ｃ１８カラム、５５ｇ、５％ＴＦＡを加えた、水中２０〜７０％ＭｅＣＮ）ことによって、白色の固体として、表題化合物を得た（３６５ｍｇ）。

HCTU (837 mg, 2.0 mmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (362 mg, 2.0 mmol) and the mixture was stirred at room temperature for 10 minutes. . DIPEA (529 μL, 3.0 mmol) and (2R, 4R) -4-amino-5- (4-bromophenyl) -2-hydroxy-pentanoic acid ethyl ester (320 mg, 1.0 mmol) were then added to produce The mixture was stirred at room temperature for 15 minutes. The mixture was concentrated in vacuo and the resulting residue was purified (C18 column, 55 g, 20-70% MeCN in water with 5% TFA added) to give the title compound as a white solid (365 mg ).

(Example 22)
(2R, 4R) -5- (5'-Chloro-2'-fluorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino]- Pentanoic acid

ＳｉｌｉｃａＣａｔ（登録商標）ＤＰＰ−Ｐｄ（０．３ｍｍｏｌ／ｇで充填；３７．４ｍｇ、１０μｍｏｌ）を、ＥｔＯＨ（５００μＬ）および水（１５０μＬ）中の（２Ｒ，４Ｒ）−５−（４−ブロモフェニル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸エチルエステル（５０．０ｍｇ、１０５μｍｏｌ）、フェニルボロン酸（１５７μｍｏｌ、１．５当量）およびＫ_２ＣＯ_３（４３．４ｍｇ、３１４μｍｏｌ）の溶液に加え、この反応混合物を１００℃で１０分間加熱した。この混合物を室温まで冷却し、この後、水中１．０ＭのＬｉＯＨ（８３８μＬ、８３８μｍｏｌ）を加え、この混合物を３０分間撹拌した。この混合物を濾過し、濾液を真空中で濃縮し、分取ＨＰＬＣで精製することによって、表題化合物を得た（１７．９ｍｇ；純度９８％）。Ｃ_２４Ｈ_２０ＣｌＦＮ_４Ｏ_５に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４９９．１１；測定値：４９９．２。

SilicaCat® DPP-Pd (packed with 0.3 mmol / g; 37.4 mg, 10 μmol) was added to (2R, 4R) -5- (4-bromophenyl) in EtOH (500 μL) and water (150 μL). 2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid ethyl ester (50.0 mg, 105 μmol), phenylboronic acid (157 μmol, 1.5 eq) and To a solution of K ₂ CO ₃ (43.4 mg, 314 μmol), the reaction mixture was heated at 100 ° C. for 10 minutes. The mixture was cooled to room temperature, after which 1.0 M LiOH in water (838 μL, 838 μmol) was added and the mixture was stirred for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (17.9 mg; purity 98%). C ₂₄ H ₂₀ ClFN ₄ against _{O 5 MS m / z [M} + H] + Calculated: 499.11; Found: 499.2.

(Example 23)
Following the procedures described in the Examples herein, the compounds having the following formula were prepared as parent compounds or as TFA salts, using appropriate starting materials and reagents instead.

１． （２Ｓ，４Ｓ）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−５−（３’−メチル−ビフェニル−４−イル）−ペンタン酸
２． （２Ｓ，４Ｓ）−５−（５’−クロロ−２’−メチル−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−１Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸
３． （２Ｓ，４Ｓ）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−５−（２’−メトキシ−ビフェニル−４−イル）−ペンタン酸
４． （２Ｓ，４Ｓ）−５−（２’，５’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸
５． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸エチルエステル
６． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸イソブチルエステル
７． （２Ｒ，４Ｒ）−５−（２’，５’−ジクロロビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸イソプロピルエステル（ＴＦＡ塩）
８． （２Ｓ，４Ｓ）−５−（３’−クロロ−５’−ヒドロキシ−ビフェニル−４−イル）−２−ヒドロキシ−４−［（３−ヒドロキシ−３Ｈ−ベンゾトリアゾール−５−カルボニル）−アミノ］−ペンタン酸。

1. (2S, 4S) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazol-5-carbonyl) -amino] -5- (3'-methyl-biphenyl-4-yl) -pentanoic acid (2S, 4S) -5- (5′-Chloro-2′-methyl-biphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-1H-benzotriazole-5-carbonyl) -amino] -Pentanoic acid (2S, 4S) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazol-5-carbonyl) -amino] -5- (2'-methoxy-biphenyl-4-yl) -pentanoic acid (2S, 4S) -5- (2 ′, 5′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid 5. (2R, 4R) -5- (2 ′, 5′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid Ethyl ester6. (2R, 4R) -5- (2 ′, 5′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid 6. Isobutyl ester (2R, 4R) -5- (2 ′, 5′-Dichlorobiphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -pentanoic acid Isopropyl ester (TFA salt)
8). (2S, 4S) -5- (3′-Chloro-5′-hydroxy-biphenyl-4-yl) -2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl) -amino] -Pentanoic acid.

Preparation 14
(S) -2- (1-biphenyl-4-yl-1-methylethyl) -5-oxo-pyrrolidine-1-carboxylic acid t-butyl ester

２−（４−ブロモフェニル）アセトニトリル（１３０．０ｇ、０．７モル）およびヨードメタン（１０３．９ｍＬ、１．７モル）のＴＨＦ（１．０Ｌ）溶液に、１０℃で、ＮａＨ（鉱油中６０％分散、６６．７ｇ、１．７モル）を少量ずつ加えた。添加完了後、この混合物を１０℃でもう２時間撹拌した。この混合物を氷水（２．０Ｌ）に注ぎ入れ、ＥｔＯＡｃ（１．５Ｌ）で抽出した。有機層を飽和水性ＮａＣｌで洗浄し、無水ＭｇＳＯ_４で乾燥させ、濃縮することによって、黄色の油として、化合物１を得た（１７５ｇ、鉱油を含有）。これをさらなる精製なしでそのまま使用した。^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ３００ ＭＨｚ） δ ７．５２ （ｄ， Ｊ ＝ ９．０ Ｈｚ， ２Ｈ）， ７．３８ （ｄ， Ｊ ＝ ９．０ Ｈｚ， ２Ｈ）， １．７２ （ｓ， ６Ｈ）。

To a solution of 2- (4-bromophenyl) acetonitrile (130.0 g, 0.7 mol) and iodomethane (103.9 mL, 1.7 mol) in THF (1.0 L) at 10 ° C. NaH (60 in mineral oil). % Dispersion, 66.7 g, 1.7 mol) was added in small portions. After the addition was complete, the mixture was stirred at 10 ° C. for another 2 hours. The mixture was poured into ice water (2.0 L) and extracted with EtOAc (1.5 L). The organic layer was washed with saturated aqueous NaCl, dried over anhydrous MgSO ₄ and concentrated to give Compound 1 as a yellow oil (175 g, containing mineral oil). This was used as is without further purification. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.52 (d, J = 9.0 Hz, 2H), 7.38 (d, J = 9.0 Hz, 2H), 1.72 (s, 6H ).

To a solution of compound 1 (175 g, containing mineral oil) in DCM (1.0 L) at −78 ° C. was added DIBAL (1.0 M solution in DCM, 700 mL, 0.70 mol) dropwise. The reaction mixture was stirred at −78 ° C. for 1.5 hours and then carefully quenched with 3.0 N HCl (1.0 L). The resulting mixture was stirred at room temperature overnight and the organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 2 as a yellow oil (180 g). This was used as is without further purification. ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.48 (s, 1H), 7.53 (d, J = 11.0 Hz, 2H), 7.17 (d, J = 11.0 Hz, 2H) ), 1.46 (s, 6H).

ＮａＣＮの水溶液（１．０ＬのＨ_２Ｏ中に３２．７ｇ、０．７モル）に、（ＮＨ_４）_２ＣＯ_３（３８０ｇ、４．０モル）および化合物２（１８０ｇ）を加えた。この反応混合物を一晩還流させ、次いで７５℃で、減圧下で濃縮した。水（３５０ｍＬ）を残渣に加え、この混合物を再度濃縮した。残渣を石油エーテル（７００ｍＬ）および水（２５０ｍＬ）中に懸濁させ、生成した混合物を室温で１５分間撹拌した。沈殿物を濾過で収集し、乾燥させることによって、白色の固体として、化合物３を得た（１５０ｇ）。^１Ｈ ＮＭＲ （ＤＭＳＯ−ｄ６， ３００ ＭＨｚ） δ １０．３９ （ｓ， １Ｈ）， ８．０５ （ｓ， １Ｈ）， ７．４８ （ｄ， Ｊ ＝ ９．０ Ｈｚ， ２Ｈ）， ７．２８ （ｄ， Ｊ ＝ ９．０ Ｈｚ， ２Ｈ）， ４．１７ （ｓ， １Ｈ）， １．４２ （ｓ， ３Ｈ）， １．３４ （ｓ， ３Ｈ）。

To an aqueous solution of NaCN (32.7 g, 0.7 mol in 1.0 L H ₂ O) was added (NH ₄ ) ₂ CO ₃ (380 g, 4.0 mol) and compound 2 (180 g). The reaction mixture was refluxed overnight and then concentrated at 75 ° C. under reduced pressure. Water (350 mL) was added to the residue and the mixture was concentrated again. The residue was suspended in petroleum ether (700 mL) and water (250 mL) and the resulting mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and dried to give compound 3 as a white solid (150 g). ¹ H NMR (DMSO-d6, 300 MHz) δ 10.39 (s, 1H), 8.05 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.28 ( d, J = 9.0 Hz, 2H), 4.17 (s, 1H), 1.42 (s, 3H), 1.34 (s, 3H).

A suspension of compound 3 (150 g, 0.51 mol) in 6.0 N NaOH (400 mL) and ethane-1,2-diol (300 mL) was stirred at 120 ° C. for 38 hours. The mixture was cooled to room temperature and neutralized with HCl solution. The precipitate was collected by filtration and dried to give compound 4 as a white solid (250 g, containing NaCl salt). ¹ H NMR (DMSO-d6, 300 MHz) δ 7.35 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 3.22 (s, 1H), 1.16 (s, 3H), 1.15 (s, 3H).

To a suspension of compound 4 (250 g, containing NaCl salt) in MeOH (1.0 L) was added dropwise thionyl chloride (72.0 mL, 1.0 mol) at 5 ° C. The mixture was refluxed overnight and the solvent was removed under reduced pressure. The residue was partitioned between DCM (1.0 L) and saturated aqueous NaHCO ₃ (1.5 L). The organic layer was washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated to give the corresponding methyl ester (90.0 g). 2-phenylacetyl chloride (48.6 g, 0.32 mol) was added to a solution of ester (90.0 g) and Et ₃ N (56.5 mL, 0.41 mol) in DCM (1.0 L) at 0 ° C. Add dropwise and stir the mixture at 0 ° C. for 30 min. The mixture was washed with 1.0 N HCl (500 mL) and saturated aqueous NaCl, respectively. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 5 (120 g). ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.32 (m, 5H), 7.18 (m, 2H), 6.95 (m, 2H), 5.68 (br s, 1H), 4. 76 (d, J = 9.0 Hz, 1H), 3.57 (s, 3H), 3.53 (d, J = 5.0 Hz, 2H), 1.30 (s, 3H), 25 (s, 3H).

化合物５（１２０ｇ、０．３０モル）のＭｅＯＨ（５００ｍＬ）溶液に、４．０Ｎ ＮａＯＨ（２００ｍＬ）を加えた。この混合物を室温で４時間撹拌し、次いで、３．０Ｎ ＨＣｌで、ｐＨをｐＨ＝１に調整した。生成した混合物をＥｔＯＡｃ（２×３００ｍＬ）で抽出した。合わせた抽出物を飽和水性ＮａＣｌで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、減圧下で濃縮した。残渣をＥｔＯＡｃ／ヘキサンから再結晶化し、化合物６を得た（８２．０ｇ）。^１Ｈ ＮＭＲ （ＤＭＳＯ−ｄ６， ３００ ＭＨｚ） δ ７．４１ （ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ）， ７．２２ （ｍ， ５Ｈ）， ６．９９ （ｄ， Ｊ ＝ ６．０ Ｈｚ， ２Ｈ）， ４．６５ （ｄ， Ｊ ＝ ９．０ Ｈｚ， １Ｈ）， ３．５２ （ｄ， Ｊ ＝ １４．０ Ｈｚ， １Ｈ）， ３．３６ （ｄ， Ｊ ＝ １４．０ Ｈｚ， １Ｈ）， １．３４ （ｓ， ３Ｈ） ， １．３０ （ｓ， ３Ｈ）。

To a solution of compound 5 (120 g, 0.30 mol) in MeOH (500 mL) was added 4.0 N NaOH (200 mL). The mixture was stirred at room temperature for 4 hours, then the pH was adjusted to pH = 1 with 3.0N HCl. The resulting mixture was extracted with EtOAc (2 × 300 mL). The combined extracts were washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was recrystallized from EtOAc / hexane to give compound 6 (82.0 g). ¹ H NMR (DMSO-d6, 300 MHz) δ 7.41 (d, J = 6.0 Hz, 2H), 7.22 (m, 5H), 6.99 (d, J = 6.0 Hz, 2H), 4.65 (d, J = 9.0 Hz, 1H), 3.52 (d, J = 14.0 Hz, 1H), 3.36 (d, J = 14.0 Hz, 1H) , 1.34 (s, 3H), 1.30 (s, 3H).

A suspension of compound 6 (82.0 g, 0.21 mol) in distilled water (3.0 L) was adjusted to pH = 8.5 using 3.0 N LiOH to form a clear solution. Immobilized penicillinase (20.0 g) was added and the resulting mixture was stirred at 37 ° C. for 60 hours. The mixture was filtered and the filtrate was adjusted to pH = 1 with 3.0N HCl and extracted with EtOAc. The combined extracts were washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 7 (59.0 g, 80% ee, containing 2-phenylacetic acid).

A suspension of compound 7 (59.0 g, containing 2-phenylacetic acid) in 6.0 N HCl (500 mL) was refluxed overnight. The mixture was washed with EtOAc (300 mL) and the aqueous phase was concentrated under reduced pressure to give the corresponding amino acid as its hydrochloride salt. The salt was dissolved in water (300 mL) and the solution was adjusted to pH = 11. A solution of (Boc) ₂ O (33.0 g, 0.2 mol) in acetone (200 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was washed with hexane (200 mL) and the aqueous phase was adjusted to pH = 2. The resulting mixture was extracted with EtOAc (2 × 300 mL). The combined extracts were washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 8 (37.0 g) as a white solid. ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.48 (br s, 1H), 7.46 (d, J = 7.0 Hz, 2H), 7.26 (d, J = 7.0 Hz, 2H), 5.02 (br s, 1H), 4.56 (d, J = 9.0 Hz, 1H), 1.39 (s, 9H).

１．０Ｎ Ｋ_２ＣＯ_３（２００ｍＬ）およびジオキサン（２００ｍＬ）中の化合物８（３７．０ｇ、０．１モル）の混合物を、窒素で３０分間脱気し、続いてフェニルボロン酸（１３．４ｇ、０．１モル）およびＰｄ（ＰＰｈ_３）_４（１．６ｇ、１．４ｍｍｏｌ）を加えた。この混合物を７５℃で８時間加熱し、次いで室温に冷却した。この混合物をＥｔＯＡｃ／ヘキサン（１５０ｍＬ、１：１）で洗浄し、水相をｐＨ＝２に調整し、ＥｔＯＡｃ（２×３００ｍＬ）で抽出した。合わせた抽出物を飽和水性ＮａＣｌで洗浄し、無水Ｎａ_２ＳＯ_４で乾燥させ、濃縮することによって、白色の固体として、化合物９を得た（３１．０ｇ、収率８４％）。

A mixture of compound 8 (37.0 g, 0.1 mol) in 1.0 N K ₂ CO ₃ (200 mL) and dioxane (200 mL) was degassed with nitrogen for 30 minutes followed by phenylboronic acid (13.4 g). 0.1 mol) and Pd (PPh ₃ ) ₄ (1.6 g, 1.4 mmol) were added. The mixture was heated at 75 ° C. for 8 hours and then cooled to room temperature. The mixture was washed with EtOAc / hexane (150 mL, 1: 1) and the aqueous phase was adjusted to pH = 2 and extracted with EtOAc (2 × 300 mL). The combined extracts were washed with saturated aqueous NaCl, dried over anhydrous Na ₂ SO ₄ and concentrated to give compound 9 as a white solid (31.0 g, 84% yield).

A solution of compound 9 (31.0 g, 84 mmol), meldrum acid (13.3 g, 92 mmol) and DMAP (15.4 g, 0.13 mol) in DCM (400 mL) was cooled to −5 ° C. and DCC (19.0 g , 92 mmol) in DCM (200 mL) was added over 1 h. The mixture was stirred at −5 ° C. overnight. The precipitate was filtered off and the filtrate was washed with 1.0 N HCl (2 × 700 mL) and saturated aqueous NaCl, respectively. The organic layer containing compound 10 was dried over anhydrous MgSO ₄ and used directly in the next step without concentration.

化合物１０のＤＣＭ（６００ｍＬ）溶液を−５℃に冷却し、ＡｃＯＨ（４５．０ｍＬ）を加えた。次いでＮａＢＨ_４（７．０ｇ、０．２モル）を３０分間にわたり少量ずつ加え、この混合物を−５℃で３時間撹拌した。水（５０．０ｍＬ）を滴下添加し、続いて飽和水性ＮａＣｌ（４５０ｍＬ）を加えた。有機層を水（２×３００ｍＬ）で洗浄し、飽和水性ＮａＨＣＯ_３（２×３００ｍＬ）で洗浄し、無水ＭｇＳＯ_４で乾燥させ、濃縮することによって、オフホワイト色の固体として、化合物１１を得た（３２．０ｇ、７５％ｅｅ）。ＥｔＯＨからの再結晶後、キラリティーの点で純粋な化合物１１を得た（１３．０ｇ）。^１Ｈ ＮＭＲ （ＣＤＣｌ_３， ３００ ＭＨｚ） δ ７．６１ （ｍ， １０Ｈ）， ４．４６ （ｂｒ ｓ， １Ｈ）， ４．２６ （ｍ， １Ｈ）， ３．７２ （ｂｒ ｓ， １Ｈ）， ２．２３ （ｍ， １Ｈ）， １．７９ （ｓ， ３Ｈ）， １．７６ （ｓ， ３Ｈ）， １．４８ （ｓ， ６Ｈ）， １．３９ （ｓ， ９Ｈ）。

A solution of compound 10 in DCM (600 mL) was cooled to −5 ° C. and AcOH (45.0 mL) was added. NaBH ₄ (7.0 g, 0.2 mol) was then added in portions over 30 minutes and the mixture was stirred at −5 ° C. for 3 hours. Water (50.0 mL) was added dropwise, followed by saturated aqueous NaCl (450 mL). The organic layer was washed with water (2 × 300 mL), washed with saturated aqueous NaHCO ₃ (2 × 300 mL), dried over anhydrous MgSO ₄ and concentrated to give compound 11 as an off-white solid. (32.0 g, 75% ee). After recrystallization from EtOH, pure compound 11 in terms of chirality was obtained (13.0 g). ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.61 (m, 10H), 4.46 (br s, 1H), 4.26 (m, 1H), 3.72 (br s, 1H), 2 .23 (m, 1H), 1.79 (s, 3H), 1.76 (s, 3H), 1.48 (s, 6H), 1.39 (s, 9H).

  A solution of compound 11 (13.0 g, 27.0 mmol) in toluene (100.0 mL) was refluxed for 3 hours. After evaporation of the solvent, the residue was recrystallized from hexane / EtOAc (3: 1) to give the title compound (8.0 g) as a white solid.

Preparation 15
(2R, 4S) -4-Amino-5-biphenyl-4-yl-2-hydroxy-5-methylhexanoic acid ethyl ester

３．０Ｎ ＨＣｌ−ＥｔＯＡｃ溶液（１５０ｍＬ）中の（Ｓ）−２−（１−ビフェニル−４−イル−１−メチルエチル）−５−オキソ−ピロリジン−１−カルボン酸ｔ−ブチルエステル（１４．０ｇ、３６．９ｍｍｏｌ、ラセミ体）の混合物を、室温で３時間撹拌した。溶媒を減圧下で除去することによって、白色の固体として化合物１（１０．０ｇ）を得た。

(S) -2- (1-biphenyl-4-yl-1-methylethyl) -5-oxo-pyrrolidine-1-carboxylic acid t-butyl ester (14. (0 g, 36.9 mmol, racemate) was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to give Compound 1 (10.0 g) as a white solid.

To a solution of compound 1 (10.0 g, 35.8 mmol) in THF (80.0 mL), BuLi (2.5 M in hexane, 15.0 mL) was added dropwise at −78 ° C. After stirring the mixture for 30 minutes, pivaloyl chloride (4.8 mL, 39.4 mmol) was added dropwise. The mixture was stirred at −78 ° C. for 1 hour and then quenched with saturated aqueous NH ₄ Cl. The resulting mixture was extracted with EtOAc and the combined extracts were washed with saturated aqueous NaCl, dried over anhydrous MgSO ₄ and concentrated. The residue was purified by silica gel flash column chromatography to give compound 2 as a white solid (9.0 g).

化合物２（９．０ｇ、２４．７ｍｍｏｌ）のＴＨＦ（５０．０ｍＬ）溶液に、−７８℃で、ナトリウムビス（トリメチルシリル）アミド（ＴＨＦ中２．０Ｍ、１８．５ｍＬ、３７．０ｍｍｏｌ）を滴下添加した。この混合物を２０分間撹拌し、オキサジリジン誘導体（１０．８ｇ、３７．０ｍｍｏｌ）のＴＨＦ（３０．０ｍＬ）溶液を滴下添加した。この混合物を−７８℃で３０分間撹拌し、次いで飽和水性ＮＨ_４Ｃｌでクエンチした。生成した混合物をＥｔＯＡｃ（１．０Ｌ）で抽出し、抽出物を１．０Ｎ ＨＣｌで洗浄し、飽和水性ＮａＣｌで洗浄し、無水ＭｇＳＯ_４で乾燥させ、蒸発させることによって、大部分の溶媒を除去した。沈殿物を濾別し、濾液を濃縮した。シリカゲルフラッシュカラムクロマトグラフィー（ＤＣＭ：ヘキサン＝１：１からＤＣＭ）で残渣を精製することによって、化合物３を得た（４．３ｇ、ラセミ体）。このラセミ体を、キラルＡＤ−カラムクロマトグラフィーにかけることによって、キラリティーの点で純粋な化合物３を得た（１．４ｇ）。^１Ｈ ＮＭＲ （ＤＭＳＯ−ｄ６， ３００ ＭＨｚ） δ ７．６３ （ｍ， ４Ｈ）， ７．４９ （ｍ， ４Ｈ）， ４．８３ （ｄ， １Ｈ）， ３．２９ （ｍ， １Ｈ）， ２．３１ （ｍ， ２Ｈ）， １．４０ （ｓ， ３Ｈ）， １．３６ （ｓ， ３Ｈ）， １．２８ （ｓ， ９Ｈ）． ＬＣ−ＭＳ（ＥＳＩ）：ｍ／ｚ ３８０．１［Ｍ＋Ｈ］^＋。

To a solution of compound 2 (9.0 g, 24.7 mmol) in THF (50.0 mL) at −78 ° C., sodium bis (trimethylsilyl) amide (2.0 M in THF, 18.5 mL, 37.0 mmol) was added dropwise. did. The mixture was stirred for 20 minutes and a solution of the oxaziridine derivative (10.8 g, 37.0 mmol) in THF (30.0 mL) was added dropwise. The mixture was stirred at −78 ° C. for 30 minutes and then quenched with saturated aqueous NH ₄ Cl. The resulting mixture is extracted with EtOAc (1.0 L) and the extract is washed with 1.0 N HCl, washed with saturated aqueous NaCl, dried over anhydrous MgSO ₄ and evaporated to remove most of the solvent. did. The precipitate was filtered off and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (DCM: hexane = 1: 1 to DCM) to give compound 3 (4.3 g, racemate). This racemate was subjected to chiral AD-column chromatography to obtain compound 3 pure in terms of chirality (1.4 g). ¹ H NMR (DMSO-d6, 300 MHz) δ 7.63 (m, 4H), 7.49 (m, 4H), 4.83 (d, 1H), 3.29 (m, 1H), 2. 31 (m, 2H), 1.40 (s, 3H), 1.36 (s, 3H), 1.28 (s, 9H). LC-MS (ESI): m / z 380.1 [M + H] &lt; ⁺ &gt;.

A solution of compound 3 (1.7 g, 160 mmol) in EtOH (15.0 mL) and 12.0 N HCl (15.0 mL) was heated at 90-95 ° C. for 20 hours. The solvent was removed and the residue was treated with 3.0 N HCl-EtOH solution (25.0 mL) for another 3 hours under reflux. After removal of the solvent, the residue was purified by preparative HPLC to give the title compound as a foamy solid HCl salt (0.6 g). ¹ H NMR (DMSO-d6, 300 MHz) δ 7.88 (br s, 3H), 7.68 (m, 4H), 7.49 (m, 4H), 7.35 (m, 1H), 6 .11 (br s, 1H), 4.11 (br s, 1H), 4.05 (q, 2H), 3.61 (br s, 1H), 1.67 (m, 2H),. 40 (s, 3H), 1.36 (s, 3H), 1.09 (t, 3H). LC-MS (ESI): m / z 342.1 [M + H] ^< +>.

(Example 24)
5-[(S) -2-biphenyl-4-yl-1-((R) -2-carboxy-2-hydroxy-ethyl) -2-methyl-propylcarbamoyl] -1H-pyrazole-3-carboxylic acid

（２Ｒ，４Ｓ）−４−アミノ−５−ビフェニル−４−イル−２−ヒドロキシ−５−メチル−ヘキサン酸エチルエステル（７０ｍｇ、０．２ｍｍｏｌ）、３，５−ピラゾールジカルボン酸（３２ｍｇ、０．２ｍｍｏｌ）、およびＨＣＴＵ（８５ｍｇ、０．２ｍｍｏｌ）をＤＭＦ（５ｍＬ）中で混合し、２分間撹拌した。ＤＩＰＥＡ（７９ｍｇ、０．６ｍｍｏｌ）を加え、生成した混合物を５０℃で１時間撹拌した。この反応混合物を減圧下で蒸発させた。粗製物をＥｔＯＨに溶解させ、十分な当量の１０Ｎ ＮａＯＨを加えることによって、混合物を塩基性にした。最終の脱保護が完了するまで、反応を１時間にわたり密にモニターした。次いでこの混合物を等量の酢酸で再酸性化し、減圧下で蒸発させた。逆相クロマトグラフィー（１０〜７０％ＭｅＣＮ勾配）を使用して、生成物を精製することによって、ＴＦＡ塩として、表題化合物を得た（１４ｍｇ；純度９０％）。Ｃ_２４Ｈ_２５Ｎ_３Ｏ_６に対するＭＳ ｍ／ｚ［Ｍ＋Ｈ］^＋計算値：４５２．１７；測定値：４５２．２。

(2R, 4S) -4-Amino-5-biphenyl-4-yl-2-hydroxy-5-methyl-hexanoic acid ethyl ester (70 mg, 0.2 mmol), 3,5-pyrazole dicarboxylic acid (32 mg, 0. 2 mmol), and HCTU (85 mg, 0.2 mmol) in DMF (5 mL) and stirred for 2 minutes. DIPEA (79 mg, 0.6 mmol) was added and the resulting mixture was stirred at 50 ° C. for 1 hour. The reaction mixture was evaporated under reduced pressure. The crude was dissolved in EtOH and the mixture was made basic by adding a sufficient equivalent of 10N NaOH. The reaction was monitored closely for 1 hour until final deprotection was complete. The mixture was then reacidified with an equal volume of acetic acid and evaporated under reduced pressure. The product was purified using reverse phase chromatography (10-70% MeCN gradient) to give the title compound as a TFA salt (14 mg; purity 90%). MS m / z for _{C 24 H 25 N 3 O 6} [M + H] + Calculated: 452.17; Found: 452.2.

(Example 25)
Following the procedures described in the Examples herein, the compounds having the following formula were prepared as parent compounds or as TFA salts, using appropriate starting materials and reagents instead.

１． （２Ｒ，４Ｓ）−５−ビフェニル−４−イル−２−ヒドロキシ−５−メチル−４−［（１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−ヘキサン酸（ＴＦＡ塩）
２． （２Ｒ，４Ｓ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（１−ヒドロキシ−１Ｈ−［１，２，３］トリアゾール−４−カルボニル）−アミノ］−５−メチル−ヘキサン酸（ＴＦＡ塩）
３． （２Ｒ，４Ｓ）−５−ビフェニル−４−イル−２−ヒドロキシ−４−［（３−ヒドロキシ−イソオキサゾール−５−カルボニル）−アミノ］−５−メチル−ヘキサン酸。

1. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-5-methyl-4-[(1H- [1,2,3] triazole-4-carbonyl) -amino] -hexanoic acid (TFA salt) )
2. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-4-[(1-hydroxy-1H- [1,2,3] triazole-4-carbonyl) -amino] -5-methyl-hexane Acid (TFA salt)
3. (2R, 4S) -5-Biphenyl-4-yl-2-hydroxy-4-[(3-hydroxy-isoxazole-5-carbonyl) -amino] -5-methyl-hexanoic acid.

Assay 1
In vitro assays for quantification of inhibitor potency (IC ₅₀ ) in human and rat NEP, and human ACE Human and rat neprilysin (EC 3.4.24.11; NEP) and compounds with human angiotensin converting enzyme (ACE) The inhibitory activity of was determined using the in vitro assay described below.

Extraction of NEP activity from rat kidney Rat NEP was prepared from adult Sprague Dawley rat kidney. Whole kidneys were washed in cold phosphate buffered saline (PBS) and ice-cold lysis buffer (1% Triton X-114, 150 mM NaCl, 50 mM Tris (hydroxymethyl) aminomethane (Tris) pH 7.5 Bordier (1981) J. Biol. Chem. 256: 1604-1607) at a ratio of 5 mL of buffer per gram of kidney. Samples were homogenized on ice using a Polytron hand-held tissue grinder. The homogenate was centrifuged at 1000 × g for 5 minutes at 3 ° C. with a swinging bucket rotor. The pellet was resuspended in 20 mL ice cold lysis buffer and incubated on ice for 30 minutes. The sample (15-20 mL) is then layered over 25 mL of ice-cold cushion buffer (6% w / v sucrose, 50 mM pH 7.5 Tris, 150 mM NaCl, 0.06%, Triton X-114). Heated to 37 ° C. for ˜5 minutes and centrifuged at 1000 × g in a swinging bucket rotor for 3 minutes at room temperature. The two upper layers were aspirated, leaving a viscous oily precipitate rich in membrane fraction. Glycerol was added to a concentration of 50% and samples were stored at -20 ° C. Protein concentration was quantified with a BCA detection system using bovine serum albumin (BSA) as a standard.

Enzyme inhibition assay Recombinant human NEP and recombinant human ACE were purchased (R & D Systems, Minneapolis, MN, catalog numbers 1182-ZN and 929-ZN, respectively). Fluorogenic peptide substrate Mca-D-Arg-Arg-Leu-Dap- (Dnp) -OH (Mediiros et al. (1997) Braz. J. Med. Biol. Res. 30: 1157-62; Anaspec, San Jose, CA) and Abz-Phe-Arg-Lys (Dnp) -Pro-OH (Arajo et al. (2000) Biochemistry, 39: 8519-8525; Bachem, Torrance, CA) for NEP and ACE assays, respectively. used.

This assay was performed using assay buffer (NEP: 50 mM HEPES, pH 7.5, 100 mM NaCl, 0.01% polyethylene glycol sorbitan monolaurate (Tween-20), 10 μM ZnSO ₄ ; ACE: 50 mM HEPES, pH 7.5, 100 mM. NaCl, 0.01% Tween-20, 1 μM ZnSO ₄ ) at 37 ° C. in a 384 well white opaque plate using a fluorogenic peptide substrate at a concentration of 10 μM. Each enzyme was used at a concentration that quantitatively proteolyzed 1 μM substrate after 20 minutes at 37 ° C.

  Test compounds were evaluated over a concentration range of 10 μM to 20 pM. Test compounds were added to the enzyme and incubated at 37 ° C. for 30 minutes before the reaction was initiated by the addition of substrate. The reaction was stopped after 20 minutes of incubation at 37 ° C. by adding glacial acetic acid to a final concentration of 3.6% (v / v).

The plate was read with a fluorimeter with excitation and emission wavelengths set to 320 nm and 405 nm, respectively. Formula (GraphPad Software, Inc., San Diego, CA):
ν = ν ₀ / [1+ (I / K ′)]
(Where ν is the reaction rate, ν ₀ is the uninhibited reaction rate, I is the inhibitor concentration, and K ′ is the apparent inhibition constant) The inhibition constant was obtained.

Compounds of the invention were tested in this assay and found to have pK _i values with human NEP as follows. In general, prodrug compounds either did not inhibit the enzyme in this in vitro assay, or the prodrug was not tested (nd) because activity was not expected.

アッセイ２
麻酔下のラットにおけるＡＣＥ活性およびＮＥＰ活性についての薬力学的（ＰＤ）アッセイ
正常血圧を有するオスのＳｐｒａｇｕｅ Ｄａｗｌｅｙラットに１２０ｍｇ／ｋｇ（ｉ．ｐ．）のイナクチンを用いて麻酔する。麻酔下においたら、頸静脈、頸動脈（ＰＥ５０管）および膀胱（フレアＰＥ５０管）のカテーテルをカニューレ処置し、気管切開術を実施して（テフロン（登録商標）針、サイズ１４ゲージ）、自発的な呼吸を促す。次いで動物に６０分間の安定化期間をもうけ、この期間中、５ｍＬ／ｋｇ／ｈの生理食塩水（０．９％）を持続的に注入し続けることによって、動物の水分補給を保ち、確実に尿を生成するようにする。加熱パッドを使用することにより、実験全体を通して体温を維持する。６０分間の安定化期間の終わりに、動物に、１５分間隔で、ＡｎｇＩ（１．０μｇ／ｋｇ、ＡＣＥ阻害剤活性）を静脈内に（ｉ．ｖ．）２回投与で投与する。ＡｎｇＩの第２回目の投与から１５分後、動物をビヒクルまたは試験化合物で処置する。５分後に、動物の心房にナトリウム利尿ペプチド（ＡＮＰ；３０μｇ／ｋｇ）のボーラスｉ．ｖ．注射でさらに処置する。ＡＮＰ処置直後から尿収集（予め秤量したエッペンドルフ管へ）を開始し、６０分間継続する。尿収集から３０分の時点および６０分の時点で、動物をＡｎｇＩで再度チャレンジする。Ｎｏｔｏｃｏｒｄシステム（Ｋａｌａｍａｚｏｏ、ＭＩ）を使用して、血圧測定をする。尿試料は、ｃＧＭＰアッセイで使用するまで−２０℃で凍結する。市販のキット（Ａｓｓａｙ Ｄｅｓｉｇｎｓ、Ａｎｎ Ａｒｂｏｒ、Ｍｉｃｈｉｇａｎ、Ｃａｔ．Ｎｏ．９０１−０１３）を使用して、酵素免疫アッセイで尿ｃＧＭＰ濃度を決定する。尿容量は、重量測定法で決定する。尿のｃＧＭＰ産出量を、尿産出量と尿ｃＧＭＰ濃度の積として計算する。ＡｎｇＩへの昇圧反応の阻害（％）を定量化することによって、ＡＣＥ阻害を評価する。ＮＥＰ阻害は、尿のｃＧＭＰ産出量におけるＡＮＰ誘発性上昇の増強を定量化することによって評価する。

Assay 2
Pharmacodynamic (PD) Assay for ACE and NEP Activity in Anesthetized Rats Male Sprague Dawley rats with normotensive blood pressure are anesthetized with 120 mg / kg (ip) inactin. Once under anesthesia, the jugular vein, carotid artery (PE50 tube) and urinary bladder (flared PE50 tube) catheters cannulated and tracheostomy performed (Teflon needle, size 14 gauge), spontaneous Encourage proper breathing. The animals were then given a 60-minute stabilization period, during which time the animals were kept hydrated and kept steadily by continuing to infuse 5 mL / kg / h saline (0.9%). Try to produce urine. Body temperature is maintained throughout the experiment by using a heating pad. At the end of the 60 minute stabilization period, the animals are given AngI (1.0 μg / kg, ACE inhibitor activity) intravenously (iv) in two doses at 15 minute intervals. Fifteen minutes after the second administration of AngI, the animals are treated with vehicle or test compound. After 5 minutes, the bolus of natriuretic peptide (ANP; 30 μg / kg) i. v. Further treatment with injection. Urine collection (into a pre-weighed Eppendorf tube) begins immediately after ANP treatment and continues for 60 minutes. Animals are challenged again with AngI at 30 and 60 minutes from urine collection. Blood pressure is measured using the Notocord system (Kalamazoo, MI). Urine samples are frozen at −20 ° C. until used in cGMP assays. Urine cGMP concentration is determined in an enzyme immunoassay using a commercially available kit (Assay Designs, Ann Arbor, Michigan, Cat. No. 901-013). Urine volume is determined gravimetrically. Urinary cGMP output is calculated as the product of urine output and urine cGMP concentration. ACE inhibition is assessed by quantifying the inhibition (%) of pressor response to AngI. NEP inhibition is assessed by quantifying the enhanced ANP-induced increase in urinary cGMP output.

Assay 3
In Vivo Evaluation of Antihypertensive Activity in a Conscious Hypertensive SHR Model Spontaneously hypertensive rats (SHR, 14-20 weeks old) are acclimatized there for at least 48 hours after arrival at the test site, Give them free access to water. For blood pressure recording, these animals are surgically implanted with a small rodent radio transmitter (telemetry unit; DSI model TA11PA-C40 or C50-PXT, Data Science Inc., USA). The tip of the catheter connected to the transmitter is inserted into the descending aorta above the iliac bifurcation and secured in place with tissue adhesive. With the nonabsorbable suture, keep the transmitter in the abdominal cavity while closing the incision in the abdominal cavity and secure it to the wall of the abdominal cavity. The outer skin is sutured closed and stapled. Animals are allowed to recover with appropriate postoperative care. On the day of the experiment, animals in these cages are placed on top of the telemetry receiver unit to acclimate to the test environment and baseline recording. After taking a baseline measurement for at least 2 hours, the animals are then dosed with vehicle or test compound, followed by blood pressure measurements for 24 hours after dosing. During the study period, data is continuously recorded and stored as electronic digital signals using Notochord software (Kalamazoo, MI). The measured parameters are blood pressure (systolic, diastolic and mean arterial pressure) and heart rate.

Assay 4
In Vivo Evaluation of Antihypertensive Activity in a Conscious Hypertensive DOCA Salt Rat Model CD rats (male, adult, 200-300 grams, Charles River Laboratory, USA) are present there for a minimum of 48 hours after arrival at the study site. Acclimate and then feed a high salt diet. One week after the start of a high salt diet (8% in food or 1% NaCl in drinking water), deoxycorticosterone acetate (DOCA) pellets (100 mg, 90 days release time, Innovative Research of America, Sarasota) , FL) is implanted subcutaneously and unilateral nephrectomy is performed. Here, the animals are also surgically implanted with a small rodent radio transmitter for blood pressure measurements (see Assay 3 for details). Animals are allowed to recover with appropriate postoperative care. Study design, data recording, and parameters to be measured are similar to those described for Assay 3.

Assay 5
In Vivo Evaluation of Antihypertensive Action in a Conscious Hypertensive Dahl / SS Rat Model Male, Dahl salt-sensitive rats (Dahl / SS, 6-7 weeks old, Charles River Laboratory, USA) arrived at the study site Acclimatized there for at least 48 hours and then fed a 8% NaCl high salt diet (TD. 92012, Harlan, USA) and then surgically implanted a small rodent radio transmitter for blood pressure measurements ( See Assay 3 for details). Animals are allowed to recover with appropriate postoperative care. Approximately 4-5 weeks after the start of the high salt diet, these animals are expected to become hypertensive. Once hypertension levels are confirmed, these animals are used in the study while continuing to maintain a high salt diet to maintain these hypertension levels. Study design, data recording, and measuring parameters are similar to those described in Assay 3.

  Although the present invention has been described with reference to particular aspects or embodiments thereof, various modifications can be made by those skilled in the art without departing from the true spirit and scope of the invention, or It will be understood that equivalents can be substituted. Further, to the extent permitted by applicable patent laws and regulations, all publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety as if each document were individually incorporated by reference. These are incorporated herein by reference in their entirety to the same extent.

Claims (30)

Compounds of formula I:

(Where
R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ ;
R ² is H or —P (O) (OH) ₂ ;
X is —C _1-9 heteroaryl,
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - NO ₂ ; —C (CH ₃ ) ═N (OH); 1 or 2 groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl in which optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; are optionally substituted with methyl or halo thiophenyl; pyrazolyl are optionally substituted with methyl furanyl; and -CH ₂ - Is selected from Ruhoriniru, R ^3, if present, bound to a carbon atom,
R ⁴ is absent or H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ OC (O) CH (R ³⁶ ) NH ₂ ; —OCH ₂ OC _{^{(O) CH (R 36)}} NH 2; -OCH 2 OC (O) CH 3; -CH 2 OP (O) (OH) 2; -CH 2 CH (OH) CH 2 OH; -CH [CH (CH _{3) 2] -NHC (O)} O-C 1~6 alkyl; pyridinyl; and _{^{halo, -COOR 35, -OCH 3, -OCF}} 3, and requires one or more groups selected from -SCF ₃ Selected from phenyl or benzyl, optionally substituted, R ⁴ , if present, is attached to a carbon or nitrogen atom;
Alternatively, when X has a total of 5 to 10 ring atoms, of which 1 to 9 are ring carbon atoms and 1 to 4 are heteroaryls that are ring heteroatoms, R on different atoms ³ and R ⁴ together form -phenylene-O- (CH ₂ ) _1-3 -or -phenylene-O-CH ₂ -CHOH-CH _2-
a is 0 or 1, R ⁵ is selected from halo, —CH ₃ , —CF ₃ , and —CN;
b is an integer of 0 or 1-3, and each R ⁶ is independently selected from halo, —OH, —CH ₃ , —OCH ₃ , and —CF ₃ ;
R ⁷ is H, —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _3-7 cycloalkyl, — [ _{(CH 2) 2 O] 1~3} CH 3, -C 1~6 alkylene _{^{-OC (O) R 10, -C}} 1~6 alkylene ^-NR 12 ^R _{13, -C} ^1~6 alkylene -C (O) R ^31, _{-C Less than six} alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

Selected from
R ¹⁰ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ¹² R ^13. , —CH [CH (CH ₃ ) ₂ ] —NH ₂ , —CH [CH (CH ₃ ) ₂ ] —NHC (O) O—C _1-6 alkyl, and —CH (NH ₂ ) CH ₂ COOCH ₃ R ¹² and R ¹³ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ¹² and R ¹³ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³¹ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 12 ^{R 13, R 32} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ⁸ is selected from H, —OH, —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, -pyridyl, and —OC (S) NR ¹⁵ R ¹⁶ , wherein R ¹⁴ is H, -C _{1 to 6 alkyl, -C 6 to 10} aryl _is selected from -OCH _{2 -C 6 to 10 aryl,} -CH _{2 O-C 6~10} aryl, and ^-NR 15 ^{R 16, R 15} and ^{R 16} _Are independently selected from H and —C _1-4 alkyl;
R ⁹ is selected from H, —C _1-6 alkyl, and —C (O) —R ¹⁷ , wherein R ¹⁷ is H, —C _1-6 alkyl, —C _3-7 cycloalkyl, —C ₆ Selected from _-10 aryl, and -C _1-9 heteroaryl,
R ²⁰ is selected from H and —C _1-6 alkyl;
R ²¹ and R ³⁵ are independently H, —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{3. -7} cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ²⁵ , -C _1-6 alkylene-NR ²⁷ R ²⁸ , -C _{1 6} alkylene-C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

Selected from
R ²⁵ is —C _1-6 alkyl, —O—C _1-6 alkyl, —C _3-7 cycloalkyl, —O—C _3-7 cycloalkyl, phenyl, —O-phenyl, —NR ²⁷ R ^28. , —CH [CH (CH ₃ ) ₂ ] —NH ₂ , —CH [CH (CH ₃ ) ₂ ] —NHC (O) O—C _1-6 alkyl, and —CH (NH ₂ ) CH ₂ COOCH ₃ R ²⁷ and R ²⁸ are independently selected from H, —C _1-6 alkyl, and benzyl, or R ²⁷ and R ²⁸ are — (CH ₂ ) _3-6 —, — C (O) — (CH ₂ ) ₃ —, or — (CH ₂ ) ₂ O (CH ₂ ) ₂ —, R ³³ is —O—C _1-6 alkyl, —O-benzyl, and it is selected from ^-NR 27 ^{R 28, R 34} are, -C _{1 6} alkyl or _{-C Less than six} alkylene _{-C 6 to 10} aryl,
R ²² and R ²³ are independently H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ SO _2. NH ₂ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _0-1 alkylene-C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ²³ together are saturated or partially unsaturated, optionally substituted with halo, —OH, —COOH, or —CONH ₂ , optionally containing an oxygen atom in the ring. -C _3-5 heterocycle is formed,
R ²⁴ is —C _1-6 alkyl; —C _0-1 alkylene-O—C _1-6 alkyl; phenyl optionally substituted with halo or —OCH ₃ ; and —C _1-9 heteroaryl Selected from
R ³⁶ is selected from H, —CH (CH ₃ ) ₂ , phenyl, and benzyl;
Each alkyl group in R ¹ , R ³ , and R ⁴ is optionally substituted with 1 to 8 fluoro atoms,
The methylene linker on biphenyl is optionally substituted with 1 or 2 —C _1-6 alkyl groups or cyclopropyl)
Or a pharmaceutically acceptable salt thereof. X is pyrazole, imidazole, triazole, benzotriazole, furan, pyrrole, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridazine, pyridine, pyrimidine, pyran, benzimidazole, benzo 2. A compound according to claim 1 selected from oxazole, benzothiazole, pyridylimidazole, and pyridyltriazole.   X is selected from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole Item 3. The compound according to Item 2. Formula III:

The compound of claim 3 having 5. The method according to claim ¹ , wherein R ¹ is selected from —OR ⁷ and —NR ⁸ R ⁹ , R ⁷ is H, R ⁸ is H or —OH, and R ⁹ is H. A compound according to one paragraph. R ¹ is —OR ⁷ and R ⁷ is —C _1-8 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _{3 -7} cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ¹⁰ , -C _1-6 alkylene-NR ¹² R ¹³ , -C _{1 6} alkylene-C (O) R ³¹ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

Or R ¹ is —NR ⁸ R ⁹ and R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, and —OC (S) NR ^15. Selected from R ¹⁶ and R ⁹ is H or R ¹ is —NR ⁸ R ⁹ and R ⁸ is —OC (O) R ¹⁴ , —CH ₂ COOH, —O-benzyl, pyridyl, And —OC (S) NR ¹⁵ R ¹⁶ , wherein R ⁹ is —C _1-6 alkyl or —C (O) R ¹⁷ , or R ¹ is —NR ⁸ R ⁹ , R ⁸ Is selected from H and —OH, and R ⁹ is selected from —C _1-6 alkyl, and —C (O) R ¹⁷ ,
The compound according to any one of claims 1 to 4. R ¹ is —OR ⁷ and R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylenemorpholinyl, —C _{1- 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, and

Selected from
_5. The compound according to claim 1, wherein R ¹⁰ is —O—C _3-7 cycloalkyl and R ³² is —CH ₃ . The compound according to any one of claims 1 to 4, wherein R ¹ is -NR ⁸ R ⁹ , R ⁸ is H, and R ⁹ is H. The compound according to any one of claims 1 to 8, wherein R ² is H. R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - NO ₂ ; —C (CH ₃ ) ═N (OH); 1 or 2 groups independently selected from halo, —OH, —CF ₃ , —OCH ₃ , —NHC (O) CH ₃ , and phenyl in which optionally substituted phenyl; naphthalenyl; pyridinyl; pyrazinyl; are optionally substituted with methyl or halo thiophenyl; pyrazolyl are optionally substituted with methyl furanyl; and -CH ₂ - Is selected from Ruhoriniru, R ²¹ is H, A compound according to any one of claims 1 9. R ³ is —C _0-1 alkylene-COOR ²¹ , R ²¹ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9. Heteroaryl, -C _3-7 cycloalkyl,-[(CH ₂ ) ₂ O] _1-3 CH ₃ , -C _1-6 alkylene-OC (O) R ²⁵ , -C _1-6 alkylene-NR ²⁷ R ^28, _{-C 1 to 6} alkylene _{^{-C (O) R 33, -C}} 0~6 alkylene _{morpholinylcarbonyl, -C 1 to 6} alkylene _-SO 2 _{-C 1 to 6} alkyl,

10. A compound according to any one of claims 1 to 9, which is selected from: R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - _{C (CH 3) = N (} OH); _{halo, -OH, -CF 3, -OCH 3} , optionally with -NHC (O) CH _3, and one or two groups independently selected from phenyl phenyl which is substituted Te; naphthalenyl; pyridinyl; pyrazinyl; thiophenyl substituted with methyl or halo; pyrazolyl substituted with methyl furanyl; and -CH 2 _- is selected from morpholinyl, R ²⁰ is A C _{1 to 6} ^{alkyl, R 21} is selected from H and _{-C 1 to 6} ^{alkyl, R 22} is selected from H and _{-C 1 to 6} ^{alkyl, R 23} is H, _{-C. 1 to 6} alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH ₃ , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _3-7 cycloalkyl, and — (CH ₂ ) selected from ₂ -imidazolyl or R ²² and R ^{23 taken} together to be azetidine, pyrrolidine, piperidine or morpholine, all of which are optionally substituted with —OH or —CONH ₂ ) is ^{formed, R 24} _{is, -C 1 to 6 alkyl;} or and pyridine; _{-C 0 to 1} alkylene _{-O-C 1 to 6} alkyl; halo or phenyl substituted with -OCH ₃ It is selected, the compounds according to any one of claims 1 to 9. R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) _CH 2 OH; pyridinyl; and _{^{halo, -COOR 35, -OCH 3, -OCF}} 3, and one or more of the phenyl or benzyl are optionally substituted with a group selected from -SCF ₃ 13. A compound according to any one of claims 1 to 12, wherein R ³⁵ is H. R ⁴ is substituted with —OCH ₂ OC (O) CH ₃ ; —CH ₂ OP (O) (OH) ₂ ; —C _1-2 alkylene-COOR ³⁵ ; and at least one —COOR ³⁵ group. Or selected from benzyl and R ³⁵ is —C _1-6 alkyl, —C _1-3 alkylene-C _6-10 aryl, —C _1-3 alkylene-C _1-9 heteroaryl, —C _3-7 cyclo. _{alkyl, - [(CH 2) 2} O] 1~3 CH 3, -C 1~6 alkylene _{^{-OC (O) R 25, -C}} 1~6 alkylene ^-NR 27 ^R _{28, -C} ^1~6 alkylene - C (O) R ³³ , —C _0-6 alkylenemorpholinyl, —C _1-6 alkylene-SO ₂ -C _1-6 alkyl,

13. A compound according to any one of claims 1 to 12, selected from: R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) CH ₂ OH; pyridinyl; phenyl optionally substituted with one halo group; and one or more selected from halo, —COOH, —OCH ₃ , —OCF ₃ , and —SCF ₃ R ³⁵ is H and R ³⁶ is —CH (CH ₃ ) ₂ or R ³ and R ⁴ on different atoms together are optionally selected from benzyl optionally substituted with becomes, the - phenylene -O- _{(CH 2)} 1~3 - or - phenylene _{-O-CH 2 -CHOH-CH 2} - to form a compound according to any one of claims 1 to 12. a or is 0, or a is 1, R ⁵ is 3-chloro, compound according to any one of claims 1 to 15. b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is 17. One of claims 1 to 16, which is 2'-fluoro-5'-chloro, 2 ', 5'-dichloro, 2'-methyl-5'-chloro, or 3'-chloro-5'-hydroxy. The compound according to item.   18. A compound according to any one of claims 1 to 17, wherein the methylene linker on the biphenyl is substituted with two methyl groups. R ¹ is —OR ⁷ and R ⁷ is H, —C _1-8 alkyl, —C _1-6 alkylene-OC (O) R ¹⁰ , —C _0-6 alkylenemorpholinyl, —C _{1- 6} alkylene _-SO 2 _{-C 1 to 6} alkyl, and

Selected from
R ¹⁰ is —O—C _3-7 cycloalkyl, R ³² is —CH ₃ , R ⁸ is H, R ⁹ is H,
R ² is H;
X is selected from pyrazole, triazole, benzotriazole, furan, tetrazole, pyrazine, thiophene, oxazole, isoxazole, thiazole, oxadiazole, pyridazine, pyridine, pyrimidine, benzoxazole, pyridylimidazole, and pyridyltriazole;
R ³ is absent or H; halo; -C _0-5 alkylene-OH; -NH ₂ ; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene _{-O-C 1 to 6 ^{alkyl; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; - _{C (CH 3) = N (} OH); _{halo, -OH, -CF 3, -OCH 3} , optionally with -NHC (O) CH _3, and one or two groups independently selected from phenyl Substituted with phenyl; naphthalenyl; pyridinyl; pyrazinyl; pyrazolyl substituted with methyl; thiophenyl substituted with methyl or halo; furanyl; and —CH ₂ -morpholinyl;
R ⁴ is absent or _H; -OH; _-C 1~6 _{alkyl; -C 1 to 2} alkylene _{^{-COOR 35; -CH 2 OC (O}} ) CH (R 36) NH 2; -CH 2 CH (OH) CH ₂ OH; pyridinyl; phenyl optionally substituted with one halo group; and one or more selected from halo, —COOH, —OCH ₃ , —OCF ₃ , and —SCF ₃ Selected from benzyl optionally substituted with a group of
Or R ³ and R ⁴ on different atoms taken together form -phenylene-O— (CH ₂ ) _1-3 — or -phenylene-O—CH ₂ —CHOH—CH ₂ —
a is 0 or a is 1 and R ⁵ is 3-chloro;
b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is 2′-fluoro-5′-chloro, 2 ′, 5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy,
R ²⁰ is —C _1-6 alkyl;
R ²¹ is selected from H and —C _1-6 alkyl;
R ²² is selected from H and —C _1-6 alkyl, and R ²³ is H, —C _1-6 alkyl, —CH ₂ COOH, — (CH ₂ ) ₂ OH, — (CH ₂ ) ₂ OCH _3. , — (CH ₂ ) ₂ N (CH ₃ ) ₂ , —C _3-7 cycloalkyl, and — (CH ₂ ) ₂ -imidazolyl, or R ²² and R ^{23 taken} together to form an azetidine , Pyrrolidine, piperidine or morpholine, all of which are optionally substituted with —OH or —CONH ₂ ,
R ²⁴ is selected from —C _1-6 alkyl; —O—C _1-6 alkyl; —CH ₂ —O—C _1-6 alkyl; phenyl substituted with halo or —OCH ₃ ; and pyridinyl;
R ³⁵ is H;
R ³⁶ is —CH (CH ₃ ) ₂ ;
The compound of claim 1, wherein the methylene linker on the biphenyl is optionally substituted with two methyl groups. R ¹ is -OR ⁷ ;
R ² is H;
X is selected from pyrazole, triazole, benzotriazole, isoxazole, pyridazine, pyrimidine, and pyridyltriazole;
R ³ is H; halo; -C _0-5 alkylene-OH; -C _1-6 alkyl; -CF ₃ ; -C _3-7 cycloalkyl; -C _0-2 alkylene-O-C _1-6 alkyl _{^{; -C (O) R 20;}} -C 0~1 alkylene ^{-COOR 21; -C (O) NR} 22 R 23; -NHC (O) R 24; = O; -C (CH 3) = N (OH ); Selected from phenyl optionally substituted with one or two groups independently selected from halo, —OH, and —OCH ₃ ; selected from pyridinyl; pyrazinyl; and thiophenyl substituted with methyl or halo And
R ⁴ is optionally substituted with H; —OH; —C _1-6 alkyl; —C _1-2 alkylene-COOR ³⁵ ; —CH ₂ CH (OH) CH ₂ OH; pyridinyl; and one halo group. R ³ and R ⁴ on different atoms are selected to form -phenylene-O— (CH ₂ ) _1-3 —
a is 0 or a is 1 and R ⁵ is 3-chloro;
b is 0, or b is 1, and R ⁶ is 3′-chloro, 3′-methyl, or 2′-methoxy, or b is 2, and R ⁶ is 2′-fluoro-5′-chloro, 2 ′, 5′-dichloro, 2′-methyl-5′-chloro, or 3′-chloro-5′-hydroxy,
R ²⁰ is —C _1-6 alkyl;
R ²¹ is H;
R ²² is selected from H and —C _1-6 alkyl; and R ²³ is selected from —C _1-6 alkyl, — (CH ₂ ) ₂ OCH ₃ , and —C _3-7 cycloalkyl, Or R ²² and R ²³ together form azetidine, pyrrolidine, or piperidine, all of which are optionally substituted with —OH or —CONH ₂ ,
R ²⁴ is phenyl substituted with halo or —OCH ₃ ;
R ³⁵ is H;
The compound of claim 1, wherein the methylene linker on the biphenyl is optionally substituted with two methyl groups. Coupling a compound of formula 1 with a compound of formula 2 to form a compound of formula I

Wherein R ¹ , R ² , X, R ³ , R ⁴ , a, R ⁵ , b and R ⁶ are as defined in claim 1 and P ¹ is H or t -Is an amino protecting group selected from butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl), and P ¹ is an amino protecting group 21. A process for preparing a compound according to any one of claims 1 to 20, further comprising the step of deprotecting the compound of formula 1. Formula 1:

Wherein R ¹ , R ² , a, R ⁵ , b and R ⁶ are as defined in claim 1 and P ¹ is H or t-butoxycarbonyl, trityl, benzyloxy 21. An amino protecting group selected from carbonyl, 9-fluorenylmethoxycarbonyl, formyl, trimethylsilyl, and t-butyldimethylsilyl) for the synthesis of compounds according to any one of claims 1-20. Useful intermediates or salts thereof.

Or a salt thereof, wherein R ¹ , R ² , X, R ³ , R ⁴ , a, R ⁵ , b and R ⁶ are as defined in claim 1 and R ^1P Is selected from —O—P ³ , —NHP ² , and —NH (O—P ⁴ ), wherein R ^3P is —C _0-5 alkylene-O—P ⁴ , —C _0-1 alkylene-COO—. Selected from P ³ and phenyl substituted with —O—P ⁴ , wherein R ^4P is substituted with —O—P ⁴ ; —C _1-2 alkylene-COO—P ³ ; and —COO—P ³ and which is selected from phenyl or benzyl, P ² is, t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl, amino selected formyl, trimethylsilyl, and t- butyldimethylsilyl A Mamorumoto, P ³ is methyl, ethyl, t- butyl, benzyl, p- methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, with t- butyldimethylsilyl, and carboxy protecting group selected from diphenylmethyl And P ⁴ is selected from —C _1-6 alkyl, tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and diphenylmethyl. 21. A process for preparing a compound according to any one of claims 1 to 20 comprising the step of deprotecting (which is a hydroxyl protecting group).

21. An intermediate useful for the synthesis of a compound according to any one of claims 1 to 20 or a salt thereof selected from: wherein R ¹ , R ² , X, R ³ , R ⁴ , a, R ⁵ , b and R ⁶ are as defined in claim 1, R ^1P is selected from —O—P ³ , —NHP ² , and —NH (O—P ⁴ ), wherein R ^3P is Selected from —C _0-5 alkylene-O—P ⁴ , —C _0-1 alkylene-COO—P ³ , and phenyl substituted with —O—P ⁴ , wherein R ^4P is —O—P ⁴ ; -C _{1 to 2} alkylene ^{-COO-P 3;} is selected from phenyl or benzyl substituted with and ^{-COO-P 3, P 2} is, t-butoxycarbonyl, trityl, benzyloxycarbonyl, 9-fluorenyl Methoxycarbonyl, formyl, trimethyl Silyl, and t-butyl dimethylamino protecting group silyl selected from, ^{P 3} is methyl, ethyl, t- butyl, benzyl, p- methoxybenzyl, 9-fluorenylmethyl, trimethylsilyl, t- butyl-dimethyl A carboxy protecting group selected from silyl and diphenylmethyl, wherein P ⁴ is —C _1-6 alkyl, tri-C _1-6 alkylsilyl, —C _1-6 alkanoyl, benzoyl, benzyl, p-methoxybenzyl, 9-fluorenylmethyl, and a hydroxyl protecting group selected from diphenylmethyl).   21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 and a pharmaceutically acceptable carrier. Adenosine receptor antagonist, α-adrenergic receptor antagonist, β ₁ -adrenergic receptor antagonist, β ₂ -adrenergic receptor agonist, dual acting β-adrenergic receptor antagonist / α ₁ -receptor antagonist, advanced glycation end product Breaker, aldosterone antagonist, aldosterone synthase inhibitor, aminopeptidase N inhibitor, androgen, angiotensin converting enzyme inhibitor and dual acting angiotensin converting enzyme / neprilysin inhibitor, angiotensin converting enzyme 2 activator and stimulator, angiotensin-II vaccine , anticoagulants, antidiabetic agents, antidiarrheals, anti-glaucoma agents, anti-lipid agents, anti-nociceptive agents, antithrombotic agents, AT ₁ receptor antagonists and dual-acting AT ₁ Toner antagonist / neprilysin inhibitor and multifunctional angiotensin receptor blocker, bradykinin receptor antagonist, calcium channel blocker, chymase inhibitor, digoxin, diuretic, dopamine agonist, endothelin converting enzyme inhibitor, endothelin receptor antagonist, HMG -CoA reductase inhibitors, estrogens, estrogen receptor agonists and / or antagonists, monoamine reuptake inhibitors, muscle relaxants, natriuretic peptides and their analogs, natriuretic peptide clearance receptor antagonists, neprilysin inhibitors, one Nitric oxide donors, non-steroidal anti-inflammatory agents, N-methyl d-aspartate receptor antagonists, opioid receptor agonists, phosphodiesterers Inhibitors, prostaglandin analogs, prostaglandin receptor agonists, renin inhibitors, selective serotonin reuptake inhibitors, sodium channel blockers, soluble guanylate cyclase stimulators and activators, tricyclic antidepressants, 26. The pharmaceutical composition of claim 25, further comprising a therapeutic agent selected from vasopressin receptor antagonists and combinations thereof. Wherein the therapeutic agent is a AT ₁ receptor antagonist, a pharmaceutical composition of claim 26. 21. A composition for use in therapy, comprising a compound according to any one of claims 1 to 20. A composition for use in the treatment of hypertension, heart failure or renal disease, comprising:
A composition comprising the compound according to 8. Claims 1 to 2 for the manufacture of a medicament for the treatment of hypertension, heart failure or kidney disease
Use of a compound according to any one of 0.